Therapeutic agents useful for treating pain

ABSTRACT

A Compound of formula  
                 
 
(wherein X is O or S and R 1 -R 5  are disclosed herein) or a pharmaceutically acceptable salt thereof (each being a “Piperazine Compound”), pharmaceutical compositions comprising a Piperazine Compound and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson&#39;s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington&#39;s chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of a Piperazine Compound are disclosed.

This application claims the benefit of U.S. Provisional Application No.60/352,855, filed Feb. 1, 2002, and U.S. Provisional Application No.60/411,043, filed Sep. 17, 2002, which are incorporated herein byreference in their entirety.

1. FIELD OF THE INVENTION

The present invention relates to Piperazine Compounds; compositionscomprising a Piperazine Compound; and methods for preventing or treatingpain, urinary incontinence (UI), an ulcer, inflammatory-bowel disease(IBD), irritable-bowel syndrome (IBS), an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia, retinopathy, a muscle spasm, a migraine,vomiting, dyskinesia or depression, comprising administering to ananimal in need thereof an effective amount of a Piperazine Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for 3 months or longer and can leadto significant changes in a patient's personality, lifestyle, functionalability and overall quality of life (K. M. Foley, Pain, in CecilTextbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed.1996)).

Pain has been traditionally managed by administering non-opioidanalgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id.

UI is uncontrollable urination, generally caused bybladder-detrusor-muscle instability. UI affects people of all ages andlevels of physical health, both in health care settings and in thecommunity at large. At present, UI afflicts 15-30% of elderly peopleliving at home, one-third of those living in acute-care settings, and atleast one-half of those living in long-term care institutions (R. M.Resnick, Lancet 346:94 (1995)). Persons having UI are predisposed toalso having urinary-tract infections, pressure ulcers, perineal rashesand urosepsis. Psychosocially, UI is associated with embarrassment,social stigmatization, depression and a risk of institutionalization(Herzo et al., Annu. Rev. Gerontol. Geriatr. 9:74 (1989)). Economically,the costs of UI are great; in the United States alone, health-care costsassociated with UI are over $15 billion per annum.

Physiologic bladder contraction results in large part fromacetylcholine-induced stimulation of post-ganglionic muscarinic-receptorsites on bladder smooth muscle. Treatments for UI include theadministration of drugs having bladder-relaxant properties, which helpto control bladder-detrusor-muscle overactivity. For example,anticholinergics such as propantheline bromide and glycopyrrolate, andcombinations of smooth-muscle relaxants such as a combination of racemicoxybutynin and dicyclomine or an anticholinergic, have been used totreat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995);Levin et al., J. Urol. 128:396-398(1982); Cooke et al., S. Afr. Med. J.63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)).These drugs are not effective, however, in all patients havinguninhibited bladder contractions. Administration of anticholinergicmedications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI, however, hasachieved complete success in all classes of UI patients, nor hastreatment occurred without significant adverse side effects. Forexample, drowsiness, dry mouth, constipation, blurred vision, headaches,tachycardia, and cardiac arrhythmia, which are related to theanticholinergic activity of traditional anti-UI drugs, can occurfrequently and adversely affect patient compliance. Yet despite theprevalence of unwanted anticholinergic effects in many patients,anticholinergic drugs are currently prescribed for patients having UI.The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

Ulcers are sores occurring where the lining of the digestive tract hasbeen eroded by stomach acids or digestive juices. The sores aretypically well-defined round or oval lesions primarily occurring in thestomach and duodenum. About 1 in 10 people develop an ulcer. Ulcersdevelop as a result of an imbalance between acid-secretory factors, alsoknown as “aggressive factors,” such as stomach acid, pepsin, andHelicobacter pylori infection, and local mucosal-protective factors,such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres toepithelial cells and is believed to form a protective coating at thebase of an ulcer to promote healing. Sucraflate, however, can causeconstipation, dry mouth, and interfere with the absorption of otherdrugs.

Antibiotics are used when Helicobacter pylori is the underlying cause ofthe ulcer. Often antibiotic therapy is coupled with the administrationof bismuth compounds such as bismuth subsalicylate and colloidal bismuthcitrate. The bismuth compounds are believed to enhance secretion ofmucous and HCO₃ ⁻, inhibit pepsin activity, and act as an antibacterialagainst H. pylori. Ingestion of bismuth compounds, however, can lead toelevated plasma concentrations of Bi⁺³ and can interfere with theabsorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acidand stimulate the secretion of mucous and bicarbonate and are also usedto treat ulcers, especially ulcers in patients who require nonsteroidalanti-inflammatory drugs. Effective oral doses of prostaglandinanalogues, however, can cause diarrhea and abdominal cramping. Inaddition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers.Carbenoxolone appears to alter the composition and quantity of mucous,thereby enhancing the mucosal barrier. Carbenoxolone, however, can leadto Na⁺ and fluid retention, hypertension, hypokalemia, and impairedglucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapinecan also be used to reduce acid secretion and treat ulcers. Side effectsof muscarinic cholinergic antagonists include dry mouth, blurred vision,and constipation. The Merck Manual of Medical Information 496-500 (R.Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis ofTherapeutics 901-915 (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

IBD is a chronic disorder in which the bowel becomes inflamed, oftencausing recurring abdominal cramps and diarrhea. The two types of IBDare Crohn's disease and ulcerative colitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominalpain, fever, loss of appetite, and weight loss. Complications associatedwith Crohn's disease include the development of intestinal obstructions,abnormal connecting channels (fistulas), and abscesses. The risk ofcancer of the large intestine is increased in people who have Crohn'sdisease. Often Crohn's disease is associated with other disorders suchas gallstones, inadequate absorption of nutrients, amyloidosis,arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyodermagangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primarysclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine. Generally, the drug is takenorally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptomsof Crohn's disease. The antibiotic metronidazole is often administeredwhen the disease affects the large intestine or causes abscesses andfistulas around the anus. Long-term use of metronidazole, however, candamage nerves, resulting in pins-and-needles sensations in the arms andlegs. Sulfasalazine and chemically related drugs can suppress mildinflammation, especially in the large intestine. These drugs, however,are less effective in sudden, severe flare-ups. Corticosteroids, such asprednisone, reduce fever and diarrhea and relieve abdominal pain andtenderness. Long-term corticosteroid therapy, however, invariablyresults in serious side effects such as high blood-sugar levels,increased risk of infection, osteoporosis, water retention, andfragility of the skin. Drugs such as azathioprine and mercaptourine cancompromise the immune system and are often effective for Crohn's diseasein patients that do not respond to other drugs. These drugs, however,usually need 3 to 6 months before they produce benefits and can causeserious side effects such as allergy, pancreatitis, and lowwhite-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely through out thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered. Sulfasalazine, olsalazie,prednisone, or mesalamine can be used to reduce inflammation.Azathioprine and mercaptopurine have been used to maintain remissions inulcerative-colitis patients who would otherwise need long-termcorticosteroid treatment. In severe cases of ulcerative colitis thepatient is hospitalized and given corticosteroids intravenously. Peoplewith severe rectal bleeding can require transfusions and intravenousfluids. If toxic colitis develops and treatments fail, surgery to removethe large intestine can be necessary. Non-emergency surgery can beperformed if cancer is diagnosed, precancerous legions are detected, orunremitting chronic disease would otherwise make the person an invalidor dependent on high doses of corticosteroids. Complete removal of thelarge intestine and rectum permanently cures ulcerative colitis. TheMerck Manual of Medical Information 530-532 (R. Berkow ed., 1997) andGoodman and Gilman's The Pharmacological Basis of Therapeutics (J.Hardman and L. Limbird eds., 9^(th) ed. 1996).

IBS is a disorder of motility of the entire gastrointestinal tract,causing abdominal pain, constipation, and/or diarrhea IBS affectsthree-times more women than men. In IBS stimuli such as stress, diet,drugs, hormones, or irritants can cause the gastrointestinal tract tocontract abnormally. During an episode of IBS contractions of thegastrointestinal tract become stronger and more frequent, resulting inthe rapid transit of food and feces through the small intestine, oftenleading to diarrhea. Cramps result from the strong contractions of thelarge intestine and increased sensitivity of pain receptors in the largeintestine.

There are two major types of IBS. The first type, spastic-colon type, iscommonly triggered by eating, and usually produces periodic constipationand diarrhea with pain. Mucous often appears in the stool. The pain cancome in bouts of continuous dull aching pain or cramps, usually in thelower abdomen. The person suffering from spastic-colon type IBS can alsoexperience bloating, gas, nausea, headache, fatigue, depression,anxiety, and difficulty concentrating. The second type of IBS usuallyproduces painless diarrhea or constipation. The diarrhea can beginsuddenly and with extreme urgency. Often the diarrhea occurs soon aftera meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS.

Antidiarrheal drugs, such as diphenoxylate and loperamide, help withdiarrhea. The Merck Manual of Medical Information 525-526 (R. Berkowed., 1997).

Many drugs can cause physical and/or psychological addiction. Those mostwell known types of these drugs include opiates, such as heroin, opium,and morphine; sympathomimetics, including cocaine and amphetamines;sedative-hypnotics, including alcohol, benzodiazepines and barbiturates;and nicotine, which has effects similar to opioids and sympathomimetics.Drug addiction is characterized by a craving or compulsion for takingthe drug and an inability to limit its intake. Additionally, drugdependence is associated with drug tolerance, the loss of effect of thedrug following repeated administration, and withdrawal, the appearanceof physical and behavioral symptoms when the drug is not consumed.Sensitization occurs if repeated administration of a drug leads to anincreased response to each dose. Tolerance, sensitization, andwithdrawal are phenomena evidencing a change in the central nervoussystem resulting from continued use of the drug. This change canmotivate the addicted individual to continue consuming the drug despiteserious social, legal, physical and/or professional consequences. (See,e.g., U.S. Pat. No. 6,109,269 to Rise et al.).

Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the substance. U.S. Pat.No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiateagonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No.5,232,934 to Downs discloses administration of 3-phenoxypyridine totreat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato etal. disclose using a serotonin antagonist to treat chemical addiction.U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF orNT-4 growth factors to inhibit or reverse neurological adaptive changesthat correlate with behavioral changes in an addicted individual. U.S.Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenalmedullary cells into an animal's central nervous system to inhibit thedevelopment of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer etal. discloses racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in theprevention or relief of a withdrawal syndrome resulting from addictionto drugs and for the treatment of chemical dependencies.

Parkinson's disease is a clinical syndrome comprising bradykinesia(slowness and poverty of movement), muscular rigidity, resting tremor(which usually abates during voluntary movement), and an impairment ofpostural balance leading to disturbance of gait and falling. Thefeatures of Parkinson's disease are a loss of pigmented, dopaminergicneurons of the substantia nigra pars compacta and the appearance ofintracellular inclusions known as Lewy bodies (Goodman and Gillman's ThePharmaceutical Basis of Therapeutics 506 (9^(th) ed. 1996)). Withouttreatment, Parkinson's disease progresses to a rigid akinetic state inwhich patients are incapable of caring for themselves. Death frequentlyresults from complications of immobility, including aspiration pneumoniaor pulmonary embolism. Drugs commonly used for the treatment ofParkinson's disease include carbidopa/levodopa, pergolide,bromocriptine, selegiline, amantadine, and trihexyphenidylhydrochloride. There remains, however, a need for drugs useful for thetreatment of Parkinson's disease and having an improved therapeuticprofile.

Anxiety is a fear, apprehension, or dread of impending danger oftenaccompanied by restlessness, tension, tachycardia, and dyspnea Othersymptoms commonly associated with anxiety include depression, especiallyaccompanied with dysthymic disorder (chronic “neurotic” depression);panic disorder; agoraphobia and other specific phobias; eatingdisorders; and many personality disorders. Often anxiety is unattachedto a clearly identified treatable primary illness. If a primary illnessis found, however, it can be desirable to deal with the anxiety at thesame time as the primary illness.

Currently, benzodiazepines are the most commonly used anti-anxietyagents for generalized anxiety disorder. Benzodiazepines, however, carrythe risk of producing impairment of cognition and skilled motorfunctions, particularly in the elderly, which can result in confusion,delerium, and falls with fractures. Sedatives are also commonlyprescribed for treating anxiety. The azapirones, such as buspirone, arealso used to treat moderate anxiety. The azapirones, however, are lessuseful for treating severe anxiety accompanied with panic attacks.

Epilepsy is a disorder characterized by the tendency to have recurringseizures. The etiology commonly consists of lesions in some part of thecortex, such as a tumor; developmental malformation; or damage due totrauma or stroke. In some cases the etiology is genetic. An epilepticseizure can be triggered by repetitive sounds, flashing lights, videogames, or touching certain parts of the body. Epilepsy is typicallytreated with anti-seizure drugs. In epilepsy cases, where anti-seizuredrugs are ineffective, and the defect in the brain is isolated to asmall area of the brain, surgical removal of that part of the brain canbe helpful in alleviating the seizures. In patients who have severalsources for the seizures or who have seizures that spread quickly to allparts of the brain, surgical removal of the nerve fibers that connectthe two sides of the brain can be helpful.

Examples of drugs for treating a seizure and epilepsy includecarbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital,phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines,γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however,can have side effects such as drowsiness; hyperactivity; hallucinations;inability to concentrate; central and peripheral nervous systemtoxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingivalhyperplasia; gastrointestinal disturbances such as nausea, vomiting,epigastric pain, and anorexia; endocrine effects such as inhibition ofantidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; andhypersensitivity such as scarlatiniform rash, morbilliform rash,Stevens-Johnson syndrome, systemic lupus erythematosus, and hepaticnecrosis; and hematological reactions such as red-cell aplasia,agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblasticanemia The Merck Manual of Medical Information 345-350 (R. Berkow ed.,1997).

A seizure is the result of abnormal electrical discharge in the brain.The discharge can involve a small area of the brain and lead to theperson only noticing an odd taste or smell or it can involve a largearea of the brain and lead to convulsions, i.e., a seizure that causesjerking and spasms of the muscles throughout the body. Convulsions canalso result in brief attacks of altered consciousness and loss ofconsciousness, muscle control, or bladder control. A seizures is oftenpreceded by auras, i.e., unusual sensations of smell, taste, or visionor an intense feeling that a seizure is about to begin. A seizuretypically lasts for about 2 to 5 minutes. When the seizure ends theperson can have headache, sore muscles, unusual sensations, confusion,and profound fatigue (postictal state). Usually the person cannotremember what happened during the seizure.

A stroke or cerebrovascular accident, is the death of brain tissue(cerebral infarction) resulting from the lack of blood flow andinsufficient oxygen to the brain. A stroke can be either ischemic orhemorrhagic. In an ischemic stroke, blood supply to the brain is cut offbecause of athersclerosis or a blood clot that has blocked a bloodvessel. In a hemorrhagic stroke, a blood vessel bursts preventing normalblood flow and allowing blood to leak into an area of the brain anddestroying it. Most strokes develop rapidly and cause brain damagewithin minutes. In some cases, however, strokes can continue to worsenfor several hours or days. Symptoms of strokes vary depending on whatpart of the brain is effected. Symptoms include loss or abnormalsensations in an arm or leg or one side of the body, weakness orparalysis of an arm or leg or one side of the body, partial loss ofvison or hearing, double vision, dizziness, slurred speech, difficultyin thinking of the appropriate word or saying it, inability to recognizeparts of the body, unusual movements, loss of bladder control,imbalance, and falling, and fainting. The symptoms can be permanent andcan be associated with coma or stupor. Strokes can cause edema orswelling of the brain which can further damage brain tissue. For personssuffering from a stroke, intensive rehabilitation can help overcome thedisability caused by impairment of brain tissue. Rehabilitation trainsother parts of the brain to assume the tasks previously performed by thedamaged part.

Examples of drugs for treating strokes include anticoagulants such asheparin, drugs that break up clots such as streptokinase or tissueplasminogen activator, and drugs that reduce swelling such as mannitolor corticosteroids. The Merck Manual of Medical Information 352-355 (R.Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching. Prurituscan be attributed to dry skin, scabies, dermatitis, herpetiformis,atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites,pediculosis, contact dermatitis, drug reactions, urticaria, urticarialeruptions of pregnancy, psoriasis, lichen planus, lichen simplexchronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, andfiberglass dermatitis. Conventionally, pruritus is treated byphototherapy with ultraviolet B or PUVA or with therapeutic agents suchas naltrexone, nalmefene, danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5(“mGluR5”) have been shown to exert analgesic activity in in vivo animalmodels (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrulet al., Neuroscience Letters, 292(2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anxiolytic and anti-depressant activity in in vivo animal models(E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) andP. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37(2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-Parkinson activity in vivo (K. J. Ossowska et al.,Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trendsin Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-dependence activity in vivo (C. Chiamulera et al., NatureNeuroscience 4(9):873-74 (2001)).

International publication no. WO 02/08221 describes diaryl piperazinecompounds and related compounds useful as selective modulators ofcapsaicin receptors and useful in the treatment of chronic and acutepain conditions, itch, and urinary incontinence.

International publication no. WO 99/37304 describes substitutedoxoazaheterocycly compounds useful for inhibiting factor Xa.

U.S. Pat. No. 6,124,299 to Baindur et al. describes piperazine compoundsthat are useful as calcitonin mimetics.

International publication no. WO 02/16318 describes urea and thioureacompounds that are modulators of the vanilloid receptor.

International publication no. WO 98/25167 describes aryl piperazinecompounds that are modulators of chemokine receptors.

U.S. Pat. No. 5,922,872 to Cook et al. describes meta-benzylic andalpha-amido compounds that are useful as antibacterials.

There remains, however, a clear need in the art for new drugs useful fortreating or preventing pain, UI, an ulcer, IBD, IBS, an addictivedisorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke,a seizure, a pruritic condition, psychosis, a cognitive disorder, amemory deficit, restricted brain function, Huntington's chorea, ALS,dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia,or depression.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds having the formula (I):

and pharmaceutically acceptable salts thereof, wherein:

R₁ is methyl or halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,        —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,        —(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl,        —(C₁-C₆)alkyl(C₁₄)aryl, —(C₁-C₆)alkyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkenyl(C₆)aryl, —(C₂-C₆)alkenyl(C₁₀)aryl,        —(C₂-C₆)alkenyl(C₁₄)aryl, —(C₂-C₆)alkenyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀) aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶; and

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(II):

and pharmaceutically acceptable salts thereof, wherein:

R₁ is methyl or halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,        —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,        —(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl,        —(C₁-C₆)alkyl(C₁₄)aryl, —(C₁-C₆)alkyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkenyl(C₆)aryl, —(C₂-C₆)alkenyl(C₁₀)aryl,        —(C₂-C₆)alkenyl(C₁₄)aryl, —(C₂-C₆)alkenyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)—(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶; and

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(III):

and pharmaceutically acceptable salts thereof, wherein:

R₁ is halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,        —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,        —(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl,        —(C₁-C₆)alkyl(C₁₄)aryl, —(C₁-C₆)alkyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkenyl(C₆)aryl, —(C₂-C₆)alkenyl(C₁₀)aryl,        —(C₂-C₆)alkenyl(C₁₄)aryl, —(C₂-C₆)alkenyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(CH₂)_(n)(C₃-C₈)cycloalkyl, —(CH₂)_(n)(C₅-C₈)cycloalkenyl,—(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶, —(CH₂)_(n)CH(halo)₂,—(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶; and

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(IV):

and pharmaceutically acceptable salts thereof, wherein:

R₁ is methyl or halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which is        unsubstituted or substituted with one or more of —CN, —OH,        -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,        —(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl,        —(C₁-C₆)alkyl(C₁₄)aryl, —(C₁-C₆)alkyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkenyl(C₆)aryl, —(C₂-C₆)alkenyl(C₁₀)aryl,        —(C₂-C₆)alkenyl(C₁₄)aryl, —(C₂-C₆)alkenyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups; or    -   (c) —(C₆)aryl, optionally substituted with one or more        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl,        —(CH₂)_(n)SR⁶, —(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo or        —(CH₂)_(n)OR⁶ groups;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶; and

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula (V):

and pharmaceutically acceptable salts thereof, wherein:

R₁ is methyl or halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₁₀)aryl,        —(C₁₄)aryl, —(C₃-C₇)heterocycle, —(C₁-C₆)alkyl(C₆)aryl,        —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,        —(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,        —(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,        —(C₂-C₆)alkenyl(C₃₋₇)heterocycle,        —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups; or    -   (c) —(C₆)aryl, optionally substituted with one or more of        —(C₂-C₆)alkenyl, —(C₂-C₆)alkyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl,        —(CH₂)_(n)SR⁶, —(CH₂)_(n)CH(halo)₂, —(CH₂)_(m)C(halo)₃, -halo,        —(CH₂)_(n)OR⁶;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, —C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶;

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(VI):

and pharmaceutically acceptable salts thereof, wherein:

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₁₀)aryl,        —(C₁₄)aryl, —(C₃-C₇)heterocycle, —(C₁C₆)alkyl(C₆)aryl,        —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,        —(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,        —(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,        —(C₂-C₆)alkenyl(C₃₋₇)heterocycle,        —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups; or    -   (c) —(C₆)aryl, optionally substituted with one or more        (C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,        —(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl,        —(CH₂)_(n)SR⁶, —(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo or        —(CH₂)_(n)OR⁶ groups;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶; and

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(VII):

and pharmaceutically acceptable salts thereof, wherein:

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

R⁵ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or    -   (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,        —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,        —(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl,        —(C₁-C₆)alkyl(C₁₄)aryl, —(C₁-C₆)alkyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkenyl(C₆)aryl, —(C₂-C₆)alkenyl(C₁₀)aryl,        —(C₂-C₆)alkenyl(C₁₄)aryl, —(C₂-C₆)alkenyl(C₃-C₇)heterocycle,        —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,        —(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,        —(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or        —(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or        substituted with one or more R⁷ groups;

each R⁶ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl,—(C₃-C₅)heterocycle, C(halo)₃, or CH(halo)₂;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)—(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶; and

n is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(VIII):

and pharmaceutically acceptable salts thereof, wherein:

X is O or S;

R¹ is —CH₃ or -halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

R⁴ is —H;

Ar is —(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₈)cycloalkyl or—(C₅-C₈)cycloalkenyl, which is unsubstituted or substituted with one ormore R⁷ groups;

each R⁵ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶;

each R⁶ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₆)aryl, —(C₁₀)aryl, or —(C₁₄)aryl;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶;

n is an integer ranging from 0 to 2; and

p is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(IX):

and pharmaceutically acceptable salts thereof, wherein:

X is O or S;

R¹ is —CH₃ or -halo;

R² is:

-   -   (a) —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶,        —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted or        substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶,        or —NR⁶OH;    -   (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted or substituted        with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶, or        —NR⁶OH; or    -   (c) —H, -halo, —NO₂, —CN, or —NH₂;

R³ is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(CH₂)_(n)OR⁶, which is unsubstituted or substituted with one or        more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or    -   (b) —H, -halo, —NO₂, —CN, or —NH₂;

Ar is —(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₈)cycloalkyl or—(C₅-C₈)cycloalkenyl, which is unsubstituted or substituted with one ormore R⁷ groups;

R⁴ is —H;

each R⁵ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶;

each R⁶ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₆)aryl, —(C₁₀)aryl, or —(C₁₄)aryl;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, —(CH₂)_(n)OR⁶;

n is an integer ranging from 0 to 2; and

p is an integer ranging from 0 to 2.

A compound of formulas (I)-(IX) or a pharmaceutically acceptable saltthereof (a “Piperazine Compound”) is useful for treating or preventingpain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression in ananimal.

The invention also relates to compositions comprising an effectiveamount of a Piperazine Compound and a pharmaceutically acceptablecarrier or excipient. The compositions are useful for treating orpreventing pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression in an animal.

The invention further relates to methods for treating pain, UI, anulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression comprisingadministering to an animal in need thereof an effective amount of aPiperazine Compound.

The invention further relates to methods for preventing pain, UI, anulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression comprisingadministering to an animal in need thereof an effective amount of aPiperazine Compound.

The invention still further relates to methods for inhibiting VanilloidReceptor 1 (“VR1”) function in a cell, comprising contacting a cellcapable of expressing VR1 with an effective amount of a PiperazineCompound.

The invention still further relates to methods for inhibiting mGluR5function in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a Piperazine Compound.

The invention still further relates to methods for inhibitingmetabotropic glutamate receptor 1 (“mGluR1”) function in a cell,comprising contacting a cell capable of expressing mGluR1 with aneffective amount of a Piperazine Compound.

The invention still further relates to a method for preparing acomposition comprising the step of admixing a Piperazine Compound and apharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a Piperazine Compound.

The present invention can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION

As stated above, the present invention encompasses compounds of Formula(I)

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove.

In one embodiment, R₁ is methyl.

In another embodiment, R₁ is halo.

In another embodiment, R₂ is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R₂ is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R₂ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which can be unsubstituted orsubstituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, R⁵ is —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl.

In another embodiment, R⁵ is —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₁-C₆) alkyl group. In another embodiment, the —(C₁-C₆) alkyl group issubstituted at the phenyl group's 4-position. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is methyl and R⁵ is phenyl. In anotherembodiment, R¹ is methyl and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹ is methyl and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹ methyl and R⁵ is phenylsubstituted with a t-butyl group at the phenyl group's 4-position.

In another embodiment, R¹ is -halo and R⁵ is phenyl. In anotherembodiment, R¹ is -halo and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-halo and R⁵ is phenyl substitutedwith a —(C₁-C₆) alkyl group at the phenyl group's 4-position. In anotherembodiment, R¹-halo and R⁵ is phenyl substituted with a t-butyl group atthe phenyl group's 4-position.

In another embodiment, R¹ is -chloro and R⁵ is phenyl. In anotherembodiment, R¹ is -chloro and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-chloro and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹-chloro and R⁵ is phenylsubstituted with a t-butyl group at the phenyl group's 4-position.

The present invention also encompasses compounds of Formula (II)

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove.

In one embodiment, R₁ is methyl.

In another embodiment, R₁ is halo.

In another embodiment, R₂ is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R₂ is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R₂ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which can be unsubstituted orsubstituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, R⁵ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl.

In another embodiment, R⁵ is —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₁-C₆) alkyl group. In another embodiment, the —(C₁-C₆) alkyl group issubstituted at the phenyl group's 4-position. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is methyl and R⁵ is phenyl. In anotherembodiment, R¹ is methyl and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹ methyl and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹ methyl and R⁵ is phenylsubstituted with a t-butyl group at the phenyl group's 4-position.

In another embodiment, R¹ is -halo and R⁵ is phenyl. In anotherembodiment, R¹ is -halo and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-halo and R⁵ is phenyl substitutedwith a —(C₁-C₆) alkyl group at the phenyl group's 4-position. In anotherembodiment, R¹-halo and R⁵ is phenyl substituted with a t-butyl group atthe phenyl group's 4-position.

In another embodiment, R¹ is -chloro and R⁵ is phenyl. In anotherembodiment, R¹ is -chloro and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-chloro and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹-chloro and R⁵ is phenylsubstituted with a t-butyl group at the phenyl group's 4-position.

The present invention also encompasses compounds of Formula (III):

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove. In a preferred embodiment, R⁵ is phenyl.

In one embodiment R¹ is -chloro.

In another embodiment, R¹ is -bromo.

In another embodiment, R¹ is -iodo.

In another embodiment, R¹ is -fluoro.

In another embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH)_(n)C(O)R⁶, (CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstituted orsubstituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which is unsubstituted or substitutedwith one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, R⁵ is —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl.

In another embodiment, R⁵ is —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₁-C₆) alkyl group. In another embodiment, the —(C₁-C₆) alkyl group issubstituted at the phenyl group's 4-position. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -chloro and R⁵ is phenyl. In anotherembodiment, R¹ is -chloro and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-chloro and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹-chloro and R⁵ is phenylsubstituted with a t-butyl group at the phenyl group's 4-position.

In another embodiment, R¹ is -bromo and R⁵ is phenyl. In anotherembodiment, R¹ is -bromo and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-bromo and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹-bromo and R⁵ is phenyl substitutedwith a t-butyl group at the phenyl group's 4-position.

In an another embodiment, R¹ is -iodo and R⁵ is phenyl. In anotherembodiment, R¹ is -iodo and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-iodo and R¹ is phenyl substitutedwith a —(C₁-C₆) alkyl group at the phenyl group's 4-position. In anotherembodiment, R¹-iodo and R⁵ is phenyl substituted with a t-butyl group atthe phenyl group's 4-position.

In another embodiment, R¹ is -fluoro and R⁵ is phenyl. In anotherembodiment, R¹ is -fluoro and R⁵ is phenyl substituted with a —(C₁-C₆)alkyl group. In another embodiment, R¹-fluoro and R⁵ is phenylsubstituted with a —(C₁-C₆) alkyl group at the phenyl group's4-position. In another embodiment, R¹-fluoro and R⁵ is phenylsubstituted with a t-butyl group at the phenyl group's 4-position.

The present invention also encompasses compounds of Formula (IV):

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove. In a preferred embodiment, R⁵ is phenyl.

In one embodiment, R₁ is methyl.

In another embodiment, R₁ is halo.

In another embodiment R¹ is -chloro.

In another embodiment, R¹ is -bromo.

In another embodiment, R¹ is -iodo.

In another embodiment, R¹ is -fluoro.

In another embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH;

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(CH₂)_(n)OR⁶, which R³ and R⁴ are each independently unsubstituted orsubstituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment R⁵ is —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl.

In another embodiment R⁵ is —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃₋₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment R⁵ is —(C₆)aryl, optionally substituted with oneor more —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo or —(CH₂)_(n)OR⁶ groups.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₂-C₆)alkenyl group. In another embodiment, the —(C₂-C₆)alkenyl groupis substituted at the phenyl group's 4-position.

In another embodiment, R¹ is methyl and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ ismethyl and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -chloro and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-chloro and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -bromo and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-bromo and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -iodo and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-iodo and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -fluoro and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-fluoro and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

The present invention also encompasses compounds of Formula (V):

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove.

In one embodiment, R₁ is methyl.

In another embodiment, R₁ is halo;

In another embodiment R¹ is -chloro.

In another embodiment, R¹ is -bromo.

In another embodiment, R¹ is -iodo.

In another embodiment, R¹ is -fluoro.

In another embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which R³ and R⁴ are each independentlyunsubstituted or substituted with one or more of —CN, —OH, -halo, —NO₂,—CH═NR⁶, or —NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, R⁵ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl.

In another embodiment, R⁵ is —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle, —(C₁-C₆)alkyl(C₆)aryl,—(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁵ is —(C₆)aryl, optionally substituted with oneor more of —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(CH₂)_(n)(C₃-C₈)cycloalkyl, —(CH₂)_(n)(C₅-C₈)cycloalkenyl,—(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶, —(CH₂)_(n)CH(halo)₂,—(CH₂)_(m)C(halo)₃, -halo, —(CH₂)_(n)OR⁶.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₂-C₆)alkenyl group. In another embodiment, the —(C₂-C₆)alkenyl groupis substituted at the phenyl group's 4-position.

In another embodiment, R¹ is methyl and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ ismethyl and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -chloro and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-chloro and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -bromo and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-bromo and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -iodo and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-iodo and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

In another embodiment, R¹ is -fluoro and R⁵ is phenyl optionallysubstituted with a —(C₂-C₆)alkenyl group. In another embodiment, R¹ is-fluoro and R⁵ is phenyl substituted with a —(C₂-C₆)alkenyl group at thephenyl group's 4-position.

The present invention also encompasses compounds of Formula (VI):

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove.

In one embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which R³ and R⁴ are each independentlyunsubstituted or substituted with one or more of —CN, —OH, -halo, —NO₂,—CH═NR⁶, or —NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, R⁵ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl.

In another embodiment, R⁵ is —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle, —(C₁-C₆)alkyl(C₆)aryl,—(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁵ is —(C₆)aryl, optionally substituted with oneor more (C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo or —(CH₂)_(n)OR⁶ groups.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₂-C₆)alkenyl group. In another embodiment, the —(C₂-C₆)alkenyl groupis substituted at the phenyl group's 4-position.

The present invention also encompasses compounds of Formula (VII):

and pharmaceutically acceptable salts thereof, where R¹-R⁵ are definedabove.

In one embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which is unsubstituted or substitutedwith one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, R⁵ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or—(C₂-C₆)alkynyl.

In another embodiment, R⁵ is —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁵ is phenyl optionally substituted with a—(C₁-C₆) alkyl group. In another embodiment, the —(C₁-C₆) alkyl group issubstituted at the phenyl group's 4-position. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

The present invention also encompasses compounds of Formula (VIII):

and pharmaceutically acceptable salts thereof, where R¹-R⁵, Ar, X and pare defined above for formula (VIII).

In one embodiment, X is O.

In another embodiment, X is S.

In another embodiment, R¹ is methyl.

In another embodiment, R¹ is halo.

In another embodiment R¹ is -chloro.

In another embodiment, R¹ is -bromo.

In another embodiment, R¹ is -iodo.

In another embodiment, R¹ is -fluoro.

In another embodiment, X is O and R¹ is methyl.

In another embodiment, X is O and R¹ is halo.

In another embodiment X is O and R¹ is -chloro.

In another embodiment, X is O and R¹ is -bromo.

In another embodiment, X is O and R¹ is -iodo.

In another embodiment, X is O and R¹ is -fluoro.

In another embodiment, X is S and R¹ is methyl.

In another embodiment, X is S and R¹ is halo.

In another embodiment X is S and R¹ is -chloro.

In another embodiment, X is S and R¹ is -bromo.

In another embodiment, X is S and R¹ is -iodo.

In another embodiment, X is S and R¹ is -fluoro.

In another embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which is unsubstituted or substitutedwith one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, Ar is —(C₆)aryl, which is unsubstituted orsubstituted with one or more R¹ groups.

In another embodiment, Ar is —(C₁₀)aryl, which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, Ar is —(C₁₄)aryl, which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, Ar is —(C₃-C₈)cycloalkyl, which is unsubstitutedor substituted with one or more R⁷ groups.

In another embodiment, Ar is —(C₅-C₈)cycloalkenyl, which isunsubstituted or substituted with one or more R⁷ groups.

In another embodiment, R¹ is methyl and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is methyl and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -halo and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -halo and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -chloro and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -chloro and Ar is phenyl, substituted inthe 4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -bromo and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -bromo and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -iodo and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -iodo and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -fluoro and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -fluoro and Ar is phenyl, substituted inthe 4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, p is 1 and R⁵ is —CH₃.

In another embodiment, p is 2 and each R⁵ is —CH₃.

The present invention also encompasses compounds of Formula (IX):

or a pharmaceutically acceptable salt thereof, where R¹-R⁵, Ar, X and pare defined above for formula (IX).

In one embodiment, X is O.

In another embodiment, X is S.

In another embodiment, R¹ is methyl.

In another embodiment, R¹ is halo.

In another embodiment R¹ is -chloro.

In another embodiment, R¹ is -bromo.

In another embodiment, R¹ is -iodo.

In another embodiment, R¹ is -fluoro.

In another embodiment, X is O and R¹ is methyl.

In another embodiment, X is O and R¹ is halo.

In another embodiment X is O and R¹ is -chloro.

In another embodiment, X is O and R¹ is -bromo.

In another embodiment, X is O and R¹ is -iodo.

In another embodiment, X is O and R¹ is -fluoro.

In another embodiment, X is S and R¹ is methyl.

In another embodiment, X is S and R¹ is halo.

In another embodiment X is S and R¹ is -chloro.

In another embodiment, X is S and R¹ is -bromo.

In another embodiment, X is S and R¹ is -iodo.

In another embodiment, X is S and R¹ is -fluoro.

In another embodiment, R² is —(C₂-C₆)alkyl, —(C₂-C₃)alkenyl,—(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which is unsubstitutedor substituted with one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or—NR⁶OH.

In another embodiment, R² is —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R² is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R₂ is —H.

In another embodiment, R³ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which is unsubstituted or substitutedwith one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH.

In another embodiment, R³ is —H, -halo, —NO₂, —CN, or —NH₂.

In another embodiment, R³ is —H.

In another embodiment, R³ is —CH₃.

In another embodiment, Ar is —(C₆)aryl, which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, Ar is —(C₁₀)aryl, which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, Ar is —(C₁₄)aryl, which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, Ar is —(C₃-C₈)cycloalkyl, which is unsubstitutedor substituted with one or more R¹ groups.

In another embodiment, Ar is —(C₅-C₈)cycloalkenyl, which isunsubstituted or substituted with one or more R⁷ groups.

In another embodiment, R¹ is methyl and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is methyl and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -halo and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -halo and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -chloro and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -chloro and Ar is phenyl, substituted inthe 4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -bromo and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -bromo and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -iodo and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -iodo and Ar is phenyl, substituted in the4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -fluoro and Ar is phenyl, optionallysubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, R¹ is -fluoro and Ar is phenyl, substituted inthe 4-position with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is a t-butyl group.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2

In another embodiment, p is 1 and R⁵ is —CH₃.

In another embodiment, p is 2 and each R⁵ is —CH₃.Illustrative Piperazine Compounds, obtainable by the methods declaredherein, are:

and pharmaceutically acceptable salts thereof.

In one embodiment the invention relates to methods for inhibiting mGluR1function in a cell comprising contacting a cell capable of expressingmGluR1 with an effective amount of a compound of formula (I)-(IX),defined above, or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to methods for inhibiting mGluR5function in a cell comprising contacting a cell capable of expressingmGluR5 with an effective amount of a compound of formula (I)-(IX),defined above, or a pharmaceutically acceptable salt thereof.

In another embodiment the invention relates to methods for treating orpreventing pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or pharmaceutically acceptable salt of acompound of formula (I)-(IX).

In another embodiment the invention relates to methods for treating orpreventing an addictive disorder, Parkinson's disease, parkinsonism,anxiety, epilepsy, stroke, a seizure, psychosis, a cognitive disorder, amemory deficit, restricted brain function, Huntington's chorea, ALS,dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia,or depression in an animal, comprising administering to an animal inneed thereof an effective amount of a compound or pharmaceuticallyacceptable salt of a compound of formula (I)-(IX).

In another embodiment the invention relates to methods for treating orpreventing pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, or psychosis in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or pharmaceutically acceptable salt of a compoundof formula (I)-(IX).

In another embodiment the invention relates to methods for treating orpreventing an addictive disorder, Parkinson's disease, parkinsonism,anxiety, or psychosis in an animal, comprising administering to ananimal in need thereof an effective amount of a compound orpharmaceutically acceptable salt of a compound of formula (I)-(IX).

Illustrative examples of compounds of formula (I) or (II) useful in theabove methods are:

and pharmaceutically acceptable salts thereof

4.1 Definitions

As used herein, the terms used above having following meaning:

“-Alkyl” means a straight chain or branched non-cyclic hydrocarbonhaving from 1 to 10 carbon atoms. “—(C₁-C₄)alkyl” means an alkyl grouphaving from 1 and 4 carbon atoms. “—(C₁-C₆)alkyl” means an alkyl grouphaving from 1 and 6 carbon atoms. “—(C₂-C₆)alkyl” means an alkyl grouphaving from 2 and 6 carbon atoms. Representative straight chain alkylsinclude -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl,-n-heptyl, -n-octyl, -n-nonly and -n-decyl; while branched alkylsinclude -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl,2-methylbutyl, and the like.

“-Alkenyl” means a straight chain or branched non-cyclic hydrocarbonhaving from 1 to 10 carbon atoms and including at lease onecarbon-carbon double bond. “—(C₂-C₆)alkenyl” means an alkenyl grouphaving from 2 and 6 carbon atoms. “—(C₂-C₃)alkenyl” means an alkenylgroup having from 2 and 3 carbon atoms. Representative straight chainand branched alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hezyl, 2-hexyl, 3-hexyl,and the like.

“-Alkynyl” means a straight chain or branched non-cyclic hydrocarbonhaving from 1 to 10 carbon atoms and including at lease onecarbon-carbon triple bond. “—(C₂-C₆)alkynyl” means an alkynyl grouphaving from 2 and 6 carbon atoms. Representative straight chain andbranched alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1 butynyl, and the like.

“-Cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 10carbon atoms. “—(C₃-C₈)cycloalkyl” means a cycloalkyl group having from3 and 8 carbon atoms. Representative cycloalkyls include -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-cyclononyl, and -cyclodecyl. Cycloalkyls also include bi- andtri-cyclic ring systems having from 8 to 14 carbon atoms such as acycloalkyl (such as cyclopentane or cyclohexane) fused to one or morearomatic (such as phenyl) or non-aromatic (such as cyclohexane)carbocyclic rings.

“-Cycloalkenyl” means a cyclic hydrocarbon having at least onecarbon-carbon double bond in the cyclic system and from 5 to 10 carbonatoms. “—(C₅-C₈)cycloalkenyl” means a cycloalkenyl group having from 5and 8 carbon atoms Representative cycloalkenyl include -cyclopentenyl,-cyclopentatienyl, -cyclohexenyl, -cyclohexadienyl, cycloheptenyl,cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl,cyclooctatrienyl, cyclooctatetraenyl, and the like. Cycloalkenyls alsoinclude bi- and tri-cyclic ring systems having from 8 to 14 carbon atomssuch as a cycloalkenyl (such as cyclopentene or cyclohexene) fused toone or more aromatic (such as phenyl) or non-aromatic (such ascyclohexane) carbocyclic rings.

“-Halogen” or “-Halo” means fluorine, chlorine, bromine or iodine.

“-Aryl” means an aromatic carbocyclic moiety such as phenyl, naphthyland anthracenyl. “—(C₆)aryl” means an aryl group having 6 carbon atoms.“—(C₁₀)aryl” means an aryl group having 10 carbon atoms. “—(C₁₄)aryl”means an aryl group having 14 carbon atoms.

“-Heteroaryl” means an aromatic heterocycle ring of 5 to 10 members andhaving at least one heteroatom selected from nitrogen, oxygen andsulfur, and containing at least 1 carbon atom, including both mono- andbicyclic ring systems. Representative heteroaryls are pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-Heterocycle” or “-Heterocyclo” means a 3- to 7-membered monocyclic, or7- to 10-membered bicyclic, heterocyclic ring which is either saturated,unsaturated, or aromatic, and which contains from 1 to 4 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen heteroatom may be optionally quaternized, including bicyclicrings in which any of the above heterocycles are fused to a benzenering. The heterocycle may be attached via any heteroatom or carbon atom.Heterocycles include heteroaryls as defined above. “—(C₃-C₅)heterocycle”means a heterocycle having from 3 and 5 ring atoms.“—(C₃-C₇)heterocycle” means a heterocycle having from 3 and 7 ringatoms. Thus, in addition to the heteroaryls listed above, heterocyclesalso include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

“-Alkylaryl” means an alkyl having at least one alkyl hydrogen atomreplaced with an aryl moiety, defined above. Illustrative -alkylarylgroups include benzyl, —(CH₂)₂phenyl, —(CH₂)₃phenyl, —CH(phenyl)₂, andthe like.

“-Alkylheterocycle” means an alkyl group wherein at least one hydrogenof the alkyl group is substituted with a heterocycle group, definedabove.

“-Alkenylaryl” means an alkenyl having at least one hydrogen atom of thealkenyl group replaced with an aryl group, defined above.

“-Alkenylheterocycle” means an alkenyl having at least one hydrogen atomof the alkenyl group replaced with an heterocycle group, defined above.

“-Alkynylcycloalkyl” means an alkynyl having at least one hydrogen atomof the alkynyl group replaced with a cycloalkyl group, defined above.

“-Alkynylcycloalkenyl” means an alkynyl having at least one hydrogenatom of the alkynyl group replaced with a cycloalkenyl group, definedabove.

“-Alkynylaryl” means an alkynyl having at least one hydrogen atom of thealkynyl group replaced with an aryl group, defined above.

“-Alkynylheterocycle” means an alkynyl having at least one hydrogen atomof the alkynyl group replaced with a heterocycle group, defined above.

The Piperazine Compounds can have a substituent, for example R₅, havinga first and a second group. Examples of substiuents having a having afirst and a second group are —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, and—(C₂-C₆)alkynyl(C₃-C₇)heterocycle., wherein each first and second groupis defined above.

Where a substituent includes a first and a second group, for example,—(C₁-C₆)alkyl(C₆)aryl, wherein (C₁-C₆)alkyl is the first group and(C₆)aryl, is the second group, it is to be understood that the firstgroup forms a bond with the Piperazine Compound's backbone and thesecond group is a substituent of the first group.

“Patient” means an animal, including, but not limited to, a cow, monkey,chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, and guinea pig, and is more preferably a mammal, andmost, preferably a human.

The phrase “pharmaceutically acceptable salt,” as used herein, is a saltformed from an acid and the basic nitrogen group of one of thePiperazine Compounds. Preferred salts include, but are not limited, tosulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also refers to a saltprepared from a Piperazine Compound having an acidic functional group,such as a carboxylic acid functional group, and a pharmaceuticallyacceptable inorganic or organic base. Suitable bases include, but arenot limited to, hydroxides of alkali metals such as sodium, potassium,and lithium; hydroxides of alkaline earth metal such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N,-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

The term “UI” means urinary incontinence.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The phrase “treatment of” and “treating” includes the amelioration orcessation of pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression, or a symptom thereof.

The phrase “prevention of” and “preventing” includes the avoidance ofthe onset of pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression, or a symptom thereof.

The phrase “effective amount,” when used in connection with a PiperazineCompound means an amount effective for: (a) treating or preventing pain,UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression; or (b)inhibiting VR1, mGluR1, or mGluR5 function in a cell.

The phrase “effective amount,” when used in connection with the anothertherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, the number of second groups is one or two. In anotherembodiment, the number of second groups is one.

The phrase “pyridyl group”, as used herein, means

wherein R¹ and R² are defined above for the Piperazine Compounds offormulas (I)-(IX).

The group

as used herein, means an ethylene group attached to a terminal Ar group,wherein one or each of two of the hydrogens of the ethylene group canoptionally be substituted with an R⁵ group.

The group

as used herein, means a n-propylene group attached to a terminal Argroup, wherein one or each of two of the hydrogens of the propylenegroup can optionally be substituted with an R⁵ group.

It is to be understood that when R² is —(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶,or —(CH₂)_(n)SR⁶; n is 0; and R⁶ is —H, then R² is unsubstituted.

4.2 Methods for Making the Piperazine Compounds

The Piperazine Compounds can be obtained using conventional organicsyntheses or by the following illustrative methods shown in the schemebelow:

wherein R₁, R₂, R₃, R₄, and R₅ are as defined above.

Compound A is reacted with Compound B in an aprotic solvent, preferablyith heating, to provide Compound C. Suitable aprotic solvents include,but are not limited to, dimethylsulfoxide (DMSO), dimethylformamide(DMF), dichloromethane (DCM), 1,2-dichloroethane, and dioxane. CompoundC is isolated from the reaction mixture and purified, preferably usingcolumn chromatography or recrystallization. Compound C is then reactedwith an isocyanate (R₅—N═C═O) or isothiocyanate (R₅—N═C═S) in a suitablesolvent, preferably dichloromethane, at a suitable temperature,preferably at room temperature, to provide the compound of Formula (I)wherein X═O or X═S, respectively.

If Compound C is substituted with a hydroxyl group or thiol group, thenthe hydroxyl or thiol group of compound B is preferably protected with asuitable protecting group before being reacted with the isocyanate orisothiocyanate. Suitable protecting groups for hydroxyl group include,but are not limited to, methyl ether, methoxymethyl ether,methoxythiomethyl ether, 2-methoxyethoxymethyl ether,bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether,tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether,methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether,tetrahydrothiofuranyl ether, 1-ethoxyethyl ether,1-methyl-1-methoxyethyl ether, 2-(phenylselenyl ether), t-butyl ether,allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether,o-napthyldiphenylmethyl ether, -methoxydiphenylmethyl ether,9-(9-phenyl-10-oxo)anthryl ether (tritylone), trimethylsilyl ether,isopropyldimethylsilyl ether, t-butyldimethylsilyl ether,t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilylether, formate ester, acetate ester, trichloroacetate ester,phenoxyacetate ester, isobutyrate ester, pivaloate ester, adamantoateester, benzoate ester, 2,4,6-trimethyl (mesitoate) ester, methylcarbonate, 2,2,2-trichlorocarbonate, allyl carbonate, p-nitrophenylcarbonate, benzyl carbonate, p-nitrobenzyl carbonate,S-benzylthiocarbonate, N-phenylcarbamate, nitrate ester, and2,4-dinitrophenylsulfenate ester (See, e.g., T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley-Interscience Publication, NewYork, (1981)).

Suitable protecting groups for thiol group include, but are not limitedto, S-benzyl thioether, S-p-methoxybenzyl thioether, S-p-nitrobenzylthioether, S-4-picolyl thioether, S-2-picolyl N-oxide thioether,S-9-anthrylmethyl thioether, S-diphenylmethyl thioether,S-di(p-methoxyphenyl)methyl thioether, S-triphenylmethyl thioether,S-2,4-dinitrophenyl thioether, S-t-butyl thioether, S-isobutoxymethylhemithioacetal, S-2tetrahydropyranyl hemithioacetal, S-acetamidomethylaminothioacetal, S-cyanomethyl thioether, S-2-nitro-1-phenylethylthioether, S-2,2-bis(carboethoxy)ethyl thioether, S-benzoyl derivative,S-(N-ethylcarbamate), and S-ethyldisulfide. Id.

Compound A wherein R₁ is Cl or CH₃ is commercially available fromAldrich Chemical Co., Milwaukee, Wis., USA; Compound A wherein R₁ is Bris commercially available from Specs B. V., Rijswijk, the Netherlands;and Compound A wherein R₁ is I is commercially available from ApolloScientific Ltd., Derbyshire, United Kingdom. Compound A wherein R₁ is Fcan be obtained by combining 3-amino 2-chloropyridine (commerciallyavailable from Aldrich Chemical Co., Milwaukee, Wis.) with HF inpyridine at 0° C., adding 1.3 eq. (based on 3-amino 2-chloropyridine) ofNaNO₂, allowing the reaction mixture to warm up to 40-45° C., andmaintaining the reaction mixture at 40-45° C. for from 10 and 30minutes.

Isocyanates R₅—N═C═O are commercially available or preparable byreacting R₅NH₂ with phosgene according to well-known methods (See, e.g.,H. Eckert and B. Foster, Angew. Chem. Int. Ed. Engl., 26, 894 (1987); H.Eckert, Ger. Offen. DE 3 440 141; Chem Abstr. 106, 4294d, (1987); and L.Contarca et al., Synthesis, 553-576 (1996)). For example an amine,R₅—NH₂ can be reacted with triphosgene according to the scheme shownbelow.

Typically, a solution of triphosgene (0.3 eq) in 1,2-dichloromethane(0.3 M) is slowly added to a stirred solution of the amine (1.0 eq.) in1,2-dichloroethane (0.3 M) at room temperature. The reaction mixture isthen stirred at room temperature for 10 min. and the temperature thenraised to 70° C. After stirring at 70° C. for 3 h., the reaction mixtureis cooled to room temperature, filtered, and the filtrate concentratedto give the desired isocyanate.

Isothiocyanates R₅—N═C═S are commercially available or preparable byreacting R₅NH2 with thiophosgene as shown in the scheme below (See,e.g., Tetrahedron. Lett., 41 (37), 7207-7209 (2000); Synlett, (11),1784-1786 (1999); Heterocycles, 32, 2343-2355 (1991); Org. Prep.,Proced., Int., 23 (6), 729-734 (1991); J. Heterocycle Chem., 28 (4),1091-1097 (1991); J. Fluorine Chem., 41 (3), 303-310 (1988); and J. Med.Chem., 32 (6) 1173-1176 and 1392-1398 (1989); and Tett. Lett., 42 (32),5414-5416 (2001).

Alternatively, isothiocyanates R₅—N═C═S can be prepared by reactingR₅NH2, with carbon disulfide in the presence of triethylamine intetrahydrofuran, followed by reaction with hydrogen peroxide andhydrochloric acid in water as shown in the scheme below (See, e.g., J.Org. Chem., 62 (13), 4539-4540 (1997)).

The Piperazine Compounds can also be prepared by reacting R₅NH₂ with4-nitophenyl chloroformate (commercially available from Aldrich ChemicalCo. of Milwaukee, Wis.) to provide a carbamate, Compound D, and thenreacting Compound D with Compound C as shown in the scheme below (See,e.g., J. Org. Chem., 63(23), 8515-8521, (1998) and European PatentPublication No. 549 039).

The scheme below illustrates methods for making the Piperazine Compoundsof formula (VIII) or (IX). These Compounds can be prepared by reactingCompound C with a phenethylamine Compound E or a phenpropylamineCompound of formula F using 4-nitrophenyl chloroformate as describedabove.

In an illustrative procedure, to a 0.5 M solution of 4-nitrophenylchloroformate in DCM at 0° C. is added a 0.5 M solution of Compound E orCompound F (1.0 eq) in DCM, followed by triethylamine (1.1 eq). Theresulting reaction is heated to 40° C. and after 5 h, the total volumeof the reaction mixture is then reduced by 50% in vacuo and Compound Cis added. The reaction mixture is stirred for 1 h at 40° C., thenconcentrated in vacuo to provide a crude residue that is purified usingflash column chromatography (gradient elution from 100% hexanes to 20%hexanes/EtOAc using a 5% gradient) to provide the corresponding compoundof formula (VIII) or (IX).

The urea or thiourea nitrogen atom of R₅ of the Piperazine Compounds canbe alkylated using sodium hydride in an anhydrous aprotic solventfollowed by reaction with an alkyl halide, such as methyl iodide.

Certain Piperazine Compounds can have one or more asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. APiperazine Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses PiperazineCompounds and their uses as described herein in the form of theiroptical isomers, diasteriomers, and mixtures thereof, including aracemic mixture.

In addition, one or more hydrogen, carbon or other atoms of a PiperazineCompound can be replaced by an isotope of the hydrogen, carbon or otheratoms. Such compounds, which are encompassed by the present invention,are useful as research and diagnostic tools in metabolismpharmacokinetic studies and in binding assays.

In the Piperazine Compounds the R³ group can be on any carbon of thepiperazine ring. In one embodiment, R³ is a group other than hydrogenand the R³ group is attached to a carbon atom adjacent to the nitrogenatom attached to the pyridyl group. In another embodiment, R³ is a groupother than hydrogen and the R³ group is attached to a carbon atomadjacent to the nitrogen atom attached to the —C(═O)—NHR₅; —C(═S)—NHR₅;—C(═O)—NH(CH₂)₂Ar group, optionally substituted with one or two R⁵groups; or —C(═O)—NH(CH₂)₃Ar group optionally substituted with one ortwo R⁵ groups.

In another embodiment, the Piperazine Compound has an R³ group that isother than hydrogen and the carbon atom to which the R³ group isattached has the (R) configuration. In another embodiment, thePiperazine Compound has an R³ group that is other than hydrogen and thecarbon atom to which the R³ group is attached has the (S) configuration.

In another embodiment, the Piperazine Compound has an R³ group that isother than hydrogen, the R³ group is attached to a carbon atom adjacentto a nitrogen atom attached to the pyridyl group, and the carbon atom towhich the R³ group is attached has the (R) configuration. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon atom to which the R³ group isattached has the (R) configuration, and R³ is —(C₁-C₄)alkylunsubstituted or substituted with one or more halo groups. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl, the carbon atom to which the R³ group isattached has the (R) configuration, and R³ is —CH₃. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon atom to which the R³ group isattached has the (R) configuration, and R³ is —CF₃. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon atom to which the R³ group isattached has the (R) configuration, and R³ is —CH₂CH₃.

In another embodiment, the Piperazine Compound has an R³ group that isother than hydrogen, the R³ group is attached to a carbon atom adjacentto a nitrogen atom attached to the —C(═O)—NHR₅; —C(═S)—NHR₅;—C(═O)—NH(CH₂)₂Ar group, optionally substituted with one or two R⁵groups; or —C(═O)—NH(CH₂)₃Ar group, optionally substituted with one ortwo R⁵ groups; and the carbon atom to which the R³ group is attached hasthe (R) configuration. In another embodiment, the Piperazine Compoundhas an R³ group other than hydrogen, the R³ group is attached to acarbon atom adjacent to a nitrogen atom attached to the —C(═O)—NHR₅;—C(═S)—NHR₅; —C(═O)—NH(CH₂)₂Ar group, optionally substituted with one ortwo R⁵ groups; or —C(═O)—NH(CH₂)₃Ar group, optionally substituted withone or two R⁵ groups; the carbon atom to which the R³ group is attachedhas the (R) configuration, and R³ is —(C₁-C₄)alkyl unsubstituted orsubstituted with one or more halo groups. In another embodiment, thePiperazine Compound has an R³ group other than hydrogen, the R³ group isattached to a carbon atom adjacent to a nitrogen atom attached to the—C(═O)—NHR₅; —C(═S)—NHR₅; —C(═O)—NH(CH₂)₂Ar group, optionallysubstituted with one or two R⁵ groups; or —C(═O)—NH(CH₂)₃Ar group,optionally substituted with one or two R⁵ groups; the carbon atom towhich the R³ group is attached has the (R) configuration, and R³ is—CH₃. In another embodiment, the Piperazine Compound has an R³ groupother than hydrogen, the R³ group is attached to a carbon atom adjacentto a nitrogen atom attached to the —C(═O)—NHR₅; —C(═S)—NHR₅;—C(═O)—NH(CH₂)₂Ar group, optionally substituted with one or two R⁵groups; or —C(═O)—NH(CH₂)₃Ar group, optionally substituted with one ortwo R⁵ groups; the carbon atom to which the R³ group is attached has the(R) configuration, and R³ is —CF₃. In another embodiment, the PiperazineCompound has an R³ group other than hydrogen, the R³ group is attachedto a carbon atom adjacent to a nitrogen atom attached to the—C(═O)—NHR₅; —C(═S)—NHR₅; —C(═O)—NH(CH₂)₂Ar group, optionallysubstituted with one or two R⁵ groups; or —C(═O)—NH(CH)₃Ar group,optionally substituted with one or two R⁵ groups; the carbon atom towhich the R³ group is attached has the (R) configuration, and R³ is—CH₂CH₃.

In another embodiment, the Piperazine Compound has an R³ group that isother than hydrogen, the R³ group is attached to a carbon atom adjacentto a nitrogen atom attached to the pyridyl group, and the carbon atom towhich the R³ group is attached has the (S) configuration. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon atom to which the R³ group isattached has the (S) configuration, and R³ is —(C₁-C₄)alkylunsubstituted or substituted with one or more halo groups. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl, the carbon atom to which the R³ group isattached has the (S) configuration, and R³ is —CH₃. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon atom to which the R³ group isattached has the (S) configuration, and R³ is —CF₃. In anotherembodiment, the Piperazine Compound has an R³ group other than hydrogen,the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon atom to which the R³ group isattached has the (S) configuration, and R³ is —CH₂CH₃.

In another embodiment, the Piperazine Compound has an R³ group that isother than hydrogen, the R³ group is attached to a carbon atom adjacentto a nitrogen atom attached to the —C(═O)—NHR₅; —C(═S)—NHR₅;—C(═O)—NH(CH₂)₂Ar group, optionally substituted with one or two R⁵groups; or —C(═O)—NH(CH₂)₃Ar group, optionally substituted with one ortwo R⁵ groups; and the carbon atom to which the R³ group is attached hasthe (S) configuration. In another embodiment, the Piperazine Compoundhas an R³ group other than hydrogen, the R³ group is attached to acarbon atom adjacent to a nitrogen atom attached to the —C(═O)—NHR₅;—C(═S)—NHR₅; —C(═O)—NH(CH₂)₂Ar group, optionally substituted with one ortwo R⁵ groups; or —C(═O)—NH(CH₂)₃Ar group, optionally substituted withone or two R⁵ groups; the carbon atom to which the R³ group is attachedhas the (S) configuration, and R³ is —(C₁-C₄)alkyl unsubstituted orsubstituted with one or more halo groups. In another embodiment, thePiperazine Compound has an R³ group other than hydrogen, the R³ group isattached to a carbon atom adjacent to a nitrogen atom attached to the—C(═O)—NHR₅; —C(═S)—NHR₅; —C(═O)—NH(CH₂)₂Ar group, optionallysubstituted with one or two R⁵ groups; or —C(═O)—NH(CH₂)₃Ar group,optionally substituted with one or two R⁵ groups; the carbon atom towhich the R³ group is attached has the (S) configuration, and R³ is—CH₃. In another embodiment, the Piperazine Compound has an R³ groupother than hydrogen, the R³ group is attached to a carbon atom adjacentto a nitrogen atom attached to the —C(═O)—NHR₅; —C(═S)—NHR₅;—C(═O)—NH(CH₂)₂Ar group, optionally substituted with one or two R⁵groups; or —C(═O)—NH(CH₂)₃Ar group, optionally substituted with one ortwo R⁵ groups; the carbon atom to which the R³ group is attached has the(S) configuration, and R³ is —CF₃. In another embodiment, the PiperazineCompound has an R³ group other than hydrogen, the R³ group is attachedto a carbon atom adjacent to a nitrogen atom attached to the—C(═O)—NHR₅; —C(═S)—NHR₅; —C(═O)—NH(CH₂)₂Ar group, optionallysubstituted with one or two R⁵ groups; or —C(═O)—NH(CH₂)₃Ar group,optionally substituted with one or two R⁵ groups; the carbon atom towhich the R³ group is attached has the (S) configuration, and R³ is—CH₂CH₃.

4.3 Therapeutic Uses of the Piperazine Compounds

In accordance with the invention, the Piperazine Compounds areadministered to an animal in need of treatment or prevention of pain,UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression.

In one embodiment, an effective amount of a Piperazine Compound can beused to treat or prevent any condition treatable or preventable byinhibiting VR1. Examples of conditions that are treatable or preventableby inhibiting VR1 include, but are not limited to, pain, UI, an ulcer,IBD, and IBS.

In another embodiment, an effective amount of a Piperazine Compound canbe used to treat or prevent any condition treatable or preventable byinhibiting mGluR5. Examples of conditions that are treatable orpreventable by inhibiting mGluR5 include, but are not limited to, pain,an addictive disorder, Parkinson's disease, parkinsonism, anxiety, apruritic condition, and psychosis.

In another embodiment, an effective amount of a Piperazine Compound canbe used to treat or prevent any condition treatable or preventable byinhibiting mGluR1. Examples of conditions that are treatable orpreventable by inhibiting mGluR1 include, but are not limited to, pain,UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, and depression.

The Piperazine Compounds can be used to treat or prevent acute orchronic pain. Examples of pain treatable or preventable using thePiperazine Compounds include, but are not limited to, cancer pain,central pain, labor pain, myocardial infarction pain, pancreatic pain,colic pain, post-operative pain, headache pain, muscle pain, painassociated with intensive care, arthritic pain, and pain associated witha periodontal disease, including gingivitis and periodontitis.

The Piperazine Compounds can be used to treat or prevent UI. Examples ofUI treatable or preventable using the Piperazine Compounds include, butare not limited to, urge incontinence, stress incontinence, overflowincontinence, neurogenic incontinence, and total incontinence.

The Piperazine Compounds can be used to treat or prevent an ulcer.Examples of ulcers treatable or preventable using the PiperazineCompounds include, but are not limited to, a duodenal ulcer, a gastriculcer, a marginal ulcer, an esophageal ulcer, or a stress ulcer.

The Piperazine Compounds can be used to treat or prevent IBD, includingCrohn's disease and ulcerative colitis.

The Piperazine Compounds can be used to treat or prevent IBS. Examplesof IBS treatable or preventable using the Piperazine Compounds include,but are not limited to, spastic-colon-type IBS andconstipation-predominant IBS.

The Piperazine Compounds can be used to treat or prevent an addictivedisorder, including but not limited to, an eating disorder, animpulse-control disorder, an alcohol-related disorder, anicotine-related disorder, an amphetamine-related disorder, acannabis-related disorder, a cocaine-related disorder, anhallucinogen-related disorder, an inhalant-related disorders, and anopioid-related disorder, all of which are further sub-classified aslisted below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and EatingDisorder not otherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse,Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium,Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Persisting Amnestic Disorder, Alcohol Dependence,Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-InducedMood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced SexualDysfunction, Alcohol-Induced Sleep Disorder, Alcohol-Related Disordernot otherwise specified (NOS), Alcohol Intoxication, and AlcoholWithdrawal.

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, Amphetamine Related Disorder not otherwise specified (NOS),Amphetamine Intoxication, and Amphetamine Withdrawal.

Cannabis-related disorders include, but are not limited to, CannabisDependence, Cannabis Abuse, Cannabis Intoxication, Cannabis IntoxicationDelirium, Cannabis-Induced Psychotic Disorder with delusions,Cannabis-Induced Psychotic Disorder with hallucinations,Cannabis-Induced Anxiety Disorder, Cannabis Related Disorder nototherwise specified (NOS), and Cannabis Intoxication.

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder,Cocaine Related Disorder not otherwise specified (NOS), CocaineIntoxication, and Cocaine Withdrawal.

Hallucinogen-related disorders include, but are not limited to,Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication,Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder with delusions,Hallucinogen-Induced Psychotic Disorders with hallucinations,Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced AnxietyDisorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-InducedSleep Disorder, Hallucinogen Related Disorder not otherwise specified(NOS), Hallucinogen Intoxication, and Hallucinogen Persisting PerceptionDisorder (Flashbacks).

Inhalant-related disorders include, but are not limited to, InhalantDependence, Inhalant Abuse, Inhalant Intoxication, Inhalant IntoxicationDelirium, Inhalant-Induced Psychotic Disorder with delusions,Inhalant-Induced Psychotic Disorder with hallucinations,Inhalant-Induced Anxiety Disorder, Inhalant Related Disorder nototherwise specified (NOS), and Inhalant Intoxication.

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Intoxication, Opioid IntoxicationDelirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, Opioid Related Disorder not otherwise specified (NOS),Opioid Intoxication, and Opioid Withdrawal.

The Piperazine Compounds can be used to treat or prevent Parkinson'sdisease and parkinsonism and the symptoms associated with Parkinson'sdisease and parkinsonism, including but not limited to, bradykinesia,muscular rigidity, resting tremor, and impairment of postural balance.

The Piperazine Compounds can be used to treat or prevent generalizedanxiety or severe anxiety and the symptoms associated with anxiety,including but not limited to, restlessness; tension; tachycardia;dyspnea; depression, including chronic “neurotic” depression; panicdisorder; agoraphobia and other specific phobias; eating disorders; andpersonality disorders.

The Piperazine Compounds can be used to treat or prevent epilepsy,including but not limited to, partial epilepsy, generalized epilepsy,and the symptoms associated with epilepsy, including but not limited to,simple partial seizures, jacksonian seizures, complex partial(psychomotor) seizures, convulsive seizures (grand mal or tonic-clonicseizures), petit mal (absence) seizures, and status epilepticus.

The Piperazine Compounds can be used to treat or prevent strokes,including but not limited to, ischemic strokes and hemorrhagic strokes.

The Piperazine Compounds can be used to treat or prevent a seizure,including but not limited to, infantile spasms, febrile seizures, andepileptic seizures.

The Piperazine Compounds can be used to treat or prevent a pruriticcondition, including but not limited to, pruritus caused by dry skin,scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvaeet ani, miliaria, insect bites, pediculosis, contact dermatitis, drugreactions, urticaria, urticarial eruptions of pregnancy, psoriasis,lichen planus, lichen simplex chronicus, exfoliative dermatitis,folliculitis, bullous pemphigoid, or fiberglass dermatitis.

The Piperazine Compounds can be used to treat or prevent psychosis,including but not limited to, schizophrenia, including paranoidschizophrenia, hebephrenic or disorganized schizophrenia, catatonicschizophrenia, undifferentiated schizophrenia, negative or deficitsubtype schizophrenia, and non-deficit schizophrenia; a delusionaldisorder, including erotomanic subtype delusional disorder, grandiosesubtype delusional disorder, jealous subtype delusional disorder,persecutory subtype delusional disorder, and somatic subtype delusionaldisorder; and brief psychosis.

The Piperazine Compounds can be used to treat or prevent a cognitivedisorder, including but not limited to, delirium and dementia such asmulti-infarct dementia, dementia pugilistica, dimentia caused by AIDS,and dementia caused by Alzheimer's disease.

The Piperazine Compounds can be used to treat or prevent a memorydeficiency, including but not limited to, dissociative amnesia anddissociative fugue.

The Piperazine Compounds can be used to treat or prevent restrictedbrain function, including but not limited to, that caused by surgery oran organ transplant, restricted blood supply to the brain, a spinal cordinjury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.

The Piperazine Compounds can be used to treat or prevent Huntington'schorea.

The Piperazine Compounds can be used to treat or prevent ALS.

The Piperazine Compounds can be used to treat or prevent retinopathy,including but not limited to, arteriosclerotic retinopathy, diabeticarteriosclerotic retinopathy, hypertensive retinopathy,non-proliferative retinopathy, and proliferative retinopathy.

The Piperazine Compounds can be used to treat or prevent a muscle spasm.

The Piperazine Compounds can be used to treat or prevent a migraine.

The Piperazine Compounds can be used to treat or prevent vomiting,including but not limited to, nausea vomiting, dry vomiting (retching),and regurgitation.

The Piperazine Compounds can be used to treat or prevent dyskinesia,including but not limited to, tardive dyskinesia and biliary dyskinesia.

The Piperazine Compounds can be used to treat or prevent depression,including but not limited to, major depression and bipolar disorder.

Applicants believe that the Piperazine Compounds are antagonists forVR1.

The invention also relates to methods for inhibiting VR1 function in acell comprising contacting a cell capable of expressing VR1 with aneffective amount of a Piperazine Compound. This method can be used invitro, for example, as an assay to select cells that express VR1 and,accordingly, are useful as part of an assay to select compounds usefulfor treating or preventing pain, UI, an ulcer, IBD, or IBS. The methodis also useful for inhibiting VR1 function in a cell in vivo, in ananimal, a human in one embodiment, by contacting a cell, in an animal,with an effective amount of a Piperazine Compound. In one embodiment,the method is useful for treating or preventing pain in an animal. Inanother embodiment, the method is useful for treating or preventing UIin an animal. In another embodiment, the method is useful for treatingor preventing an ulcer in an animal. In another embodiment, the methodis useful for treating or preventing IBD in an animal. In anotherembodiment, the method is useful for treating or preventing IBS in ananimal.

Examples of tissue comprising cells capable of expressing VR1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express VR1 are well known inthe art.

Applicants believe that the Piperazine Compounds are antagonists formGluR5.

The invention also relates to methods for inhibiting mGluR5 function ina cell comprising contacting a cell capable of expressing mGluR5 with anamount of a Piperazine Compound effective to inhibit mGluR5 function inthe cell. This method can be used in vitro, for example, as an assay toselect cells that express mGluR5 and, accordingly, are useful as part ofan assay to select compounds useful for treating or preventing pain, anaddictive disorder, Parkinson's disease, parkinsonism, anxiety, apruritic condition, or psychosis. The method is also useful forinhibiting mGluR5 function in a cell in vivo, in an animal, a human inone embodiment, by contacting a cell, in an animal, with an amount of apiperazine Compound effective to inhibit mGluR5 function in the cell. Inone embodiment, the method is useful for treating or preventing pain inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing an addictive disorder in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing Parkinson's disease in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing parkinsonismin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing anxiety in an animal in need thereof.In another embodiment, the method is useful for treating or preventing apruritic condition in an animal in need thereof. In another embodiment,the method is useful for treating or preventing psychosis in an animalin need thereof.

Examples of cells capable of expressing mGluR5 are neuronal and glialcells of the central nervous system, particularly the brain, especiallyin the nucleus accumbens. Methods for assaying cells that express mGluR5are well known in the art.

Applicants believe that the Piperazine Compounds are antagonists formGluR1.

The invention also relates to methods for inhibiting mGluR1 function ina cell comprising contacting a cell capable of expressing mGluR1 with anamount of a Piperazine Compound effective to inhibit mGluR1 function inthe cell. This method can be used in vitro, for example, as an assay toselect cells that express mGluR1 and, accordingly, are useful as part ofan assay to select compounds useful for treating or preventing pain, UI,an addictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, or depression. The method is also usefulfor inhibiting mGluR1 function in a cell in vivo, in an animal, a humanin one embodiment, by contacting a cell, in an animal, with an amount ofa Piperazine Compound effective to inhibit mGluR1 function in the cell.In one embodiment, the method is useful for treating or preventing painin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing UI in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing anaddictive disorder in an animal in need thereof. In another embodiment,the method is useful for treating or preventing Parkinson's disease inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing parkinsonism in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventinganxiety in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing epilepsy in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing stroke in an animal in need thereof. In another embodiment,the method is useful for treating or preventing a seizure in an animalin need thereof. In another embodiment, the method is useful fortreating or preventing a pruritic condition in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing psychosis in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a cognitivedisorder in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing a memory deficit in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing restricted brain function in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventingHuntington's chorea in an animal in need thereof. In another embodiment,the method is useful for treating or preventing ALS in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing dementia in an animal in need thereof. In another embodiment,the method is useful for treating or preventing retinopathy in an animalin need thereof. In another embodiment, the method is useful fortreating or preventing a muscle spasm in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing amigraine in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing vomiting in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing dyskinesia in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing depressionin an animal in need thereof.

Examples of cells capable of expressing mGluR1 include, but are notlimited to, cerebellar Purkinje neuron cells, Purkinje cell bodies(punctate), cells of spine(s) of the cerebellum; neurons and neurophilcells of olfactory-bulb glomeruli; cells of the superficial layer of thecerebral cortex; hippocampus cells; thalamus cells; superior colliculuscells; and spinal trigeminal nucleus cells. Methods for assaying cellsthat express mGluR1 are well known in the art.

4.3.1 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Piperazine Compounds are advantageouslyuseful in veterinary and human medicine. As described above, thePiperazine Compounds are useful for treating or preventing pain, UI, anulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression in ananimal in need thereof.

When administered to an animal, the Piperazine Compounds areadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a Piperazine Compound, can be administeredorally. The Piperazine Compounds of the invention can also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral, rectal, and intestinal mucosa, etc.) and can beadministered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the Piperazine Compound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of the Piperazine Compounds into the bloodstream.

In specific embodiments, it can be desirable to administer thePiperazine Compounds locally. This can be achieved, for example, and notby way of limitation, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository orenema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the PiperazineCompounds into the central nervous system or gastrointestinal tract byany suitable route, including intraventricular, intrathecal, andepidural injection, and enema. Intraventricular injection can befacilitated by an intraventricular catheter, for example, attached to areservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Piperazine Compounds can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the Piperazine Compounds can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990) and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the Piperazine Compounds can be delivered ina controlled-release system or sustained-release system (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 (1984)). Other controlled- or sustained-release systemsdiscussed in the review by Langer, Science 249:1527-1533 (1990) can beused. In one embodiment, a pump can be used (Langer, Science249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J.Med. 321:574 (1989)). In another embodiment, polymeric materials can beused (see Medical Applications of Controlled Release (Langer and Wiseeds., 1974); Controlled Drug Bioavailability, Drug Product Design andPerformance (Smolen and Ball eds., 1984); Ranger and Peppas, J.Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard etal., J. Neurosurg. 71:105 (1989)). In yet another embodiment, acontrolled- or sustained-release system can be placed in proximity of atarget of the Piperazine Compounds, e.g., the spinal column, brain, orgastrointestinal tract, thus requiring only a fraction of the systemicdose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to an animal. Water is a particularlyuseful excipient when the Piperazine Compound is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The present compositions, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule (seee.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the Piperazine Compounds are formulated in accordancewith routine procedures as a composition adapted for oral administrationto human beings. Compositions for oral delivery can be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

In another embodiment, the Piperazine Compounds can be formulated forintravenous administration. Typically, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lignocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherethe Piperazine Compounds are to be administered by infusion, they can bedispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the Piperazine Compounds areadministered by injection, an ampule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

The Piperazine Compounds can be administered by controlled-release orsustained-release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of whichis incorporated herein by reference. Such dosage forms can be used toprovide controlled- or sustained-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled- or sustained-release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the active ingredients of the invention.The invention thus encompasses single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled- orsustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained counterparts. In one embodiment, acontrolled- or sustained-release composition comprises a minimal amountof a Piperazine Compound to cure or control the condition in a minimumamount of time. Advantages of controlled- or sustained-releasecompositions include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition, controlled- orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of the PiperazineCompound, and can thus reduce the occurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a Piperazine Compound that promptly produces the desiredtherapeutic or prophylactic effect, and gradually and continuallyrelease other amounts of the Piperazine Compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.To maintain a constant level of the Piperazine Compound in the body, thePiperazine Compound can be released from the dosage form at a rate thatwill replace the amount of Piperazine Compound being metabolized andexcreted from the body. Controlled- or sustained-release of an activeingredient can be stimulated by various conditions, including but notlimited to, changes in pH, changes in temperature, concentration oravailability of enzymes, concentration or availability of water, orother physiological conditions or compounds.

The amount of the Piperazine Compound that is effective in the treatmentor prevention of pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression and can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays can optionally be employed to helpidentify optimal dosage ranges. The precise dose to be employed willalso depend on the route of administration, and the seriousness of thecondition being treated and should be decided according to the judgmentof the practitioner and each patient's circumstances in view of, e.g.,published clinical studies. Suitable effective dosage amounts, however,range from about 10 micrograms to about 2500 milligrams about every 4 h,although they are typically about 100 mg or less. In one embodiment, theeffective dosage amount ranges from about 0.01 milligrams to about 100milligrams of a Piperazine Compound about every 4 h, in anotherembodiment, about 0.020 milligrams to about 50 milligrams about every 4h, and in another embodiment, about 0.025 milligrams to about 20milligrams about every 4 h. The effective dosage amounts describedherein refer to total amounts administered; that is, if more than onePiperazine Compound is administered, the effective dosage amountscorrespond to the total amount administered.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Piperazine Compound in vitro, the amount effective for inhibitingthe receptor function in a cell will typically range from about 0.01μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/L to about2.5 mg/L, in another embodiment, from about 0.01 μg/L to about 0.5 mg/L,and in another embodiment, from about 0.01 μg/L to about 0.25 mg/L of asolution or suspension of a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspension isfrom about 1 μL to about 1 mL. In another embodiment, the volume ofsolution or suspension is about 200 μL.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Piperazine Compound in vivo, the amount effective for inhibitingthe receptor function in a cell will typically range from about 0.01 mgto about 100 mg/kg of body weight per day, in one embodiment, from about0.1 mg to about 50 mg/kg body weight per day, and in another embodiment,from about 1 mg to about 20 mg/kg of body weight per day.

The Piperazine Compounds can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.

The present methods for treating or preventing pain, UI, an ulcer, IBD,IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, or depression in an animal in needthereof can further comprise administering to the animal beingadministered a Piperazine Compound another therapeutic agent. In oneembodiment, the other therapeutic agent is administered in an effectiveamount.

The present methods for inhibiting VR1 function in a cell capable ofexpressing VR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR5 function in a cell capable ofexpressing mGluR5 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR1 function in a cell capable ofexpressing mGluR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The other therapeutic agent includes, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroid anti-inflammatory agent,an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker,an anticancer agent, an agent for treating or preventing UI, an agentfor treating or preventing an ulcer, an agent for treating or preventingIBD, an agent for treating or preventing IBS, an agent for treatingaddictive disorder, an agent for treating Parkinson's disease andparkinsonism, an agent for treating anxiety, an agent for treatingepilepsy, an agent for treating a stroke, an agent for treating aseizure, an agent for treating a pruritic condition, an agent fortreating psychosis, an agent for treating Huntington's chorea, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, and mixturesthereof.

Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective-amount range. In one embodiment of the invention, whereanother therapeutic agent is administered to an animal, the effectiveamount of the Piperazine Compound is less than its effective amountwould be where the other therapeutic agent is not administered. In thiscase, without being bound by theory, it is believed that the PiperazineCompounds and the other therapeutic agent act synergistically to treator prevent pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine,ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine,lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixturesthereof.

The other therapeutic agent can also be an agent useful for reducing anypotential side effects of a Piperazine Compounds. For example, the othertherapeutic agent can be an antiemetic agent. Examples of usefulantiemetic agents include, but are not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, piparnazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytyptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine,indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan,oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine,iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,pheneizine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbarnate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful Ca2+-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexiline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alfa-2a, interferonalfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofirin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspernine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy, mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine;prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful anti-anxiety agents include, but are not limited to,benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide,clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam,flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam,nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam;non-benzodiazepine agents, such as buspirone, gepirone, ipsaprione,tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such asbarbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital,mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital,and thiopental; and propanediol carbamates, such as meprobamate andtybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumerate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as ondansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazin, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotilinr, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlaflaxine; selectiveserotonin reuptake inhibitors such as fluoxetine, fluvoxamine,paroxetine, and setraline; monoamine oxidase inhibitors such asisocarboxazid, pargyline, phenelzine, and tranylcypromine; andpsychostimulants such as dextroamphetamine and methylphenidate.

A Piperazine Compound and the other therapeutic agent can act additivelyor, in one embodiment, synergistically. In one embodiment, a PiperazineCompound is administered concurrently with another therapeutic agent. Inone embodiment, a composition comprising an effective amount of aPiperazine Compound and an effective amount of another therapeutic agentcan be administered. Alternatively, a composition comprising aneffective amount of a Piperazine Compound and a different compositioncomprising an effective amount of another therapeutic agent can beconcurrently administered. In another embodiment, an effective amount ofa Piperazine Compound is administered prior or subsequent toadministration of an effective amount of another therapeutic agent.

4.3.2 Kits

The invention encompasses kits that can simplify the administration of aPiperazine Compound to an animal.

A typical kit of the invention comprises a unit dosage form of aPiperazine Compound. In one embodiment, the unit dosage form is acontainer, which can be sterile, containing an effective amount of aPiperazine Compound and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the Piperazine Compound to treat pain, UI, anulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression. The kitcan also further comprise a unit dosage form of another therapeuticagent, for example, a container containing an effective amount of theother therapeutic agent. In one embodiment, the kit comprises acontainer containing an effective amount of a Piperazine Compound and aneffective amount of another therapeutic agent. Examples of othertherapeutic agents include, but are not limited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device includes,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not, of course, be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of all equivalents now knownor later developed, which would be within the purview of those skilledin the art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

Examples 1-7 relate to the synthesis of illustrative PiperazineCompounds.

5.1 Example 1 Synthesis of Compounds 1c-1k

2,3-Dichloropyridine 1a (0.22 g, 1.45 mmol) and 1.1 eq. of piperazine(0.14 g, 1.59 mmol) were dissolved in 3 mL of dimethyl sulfoxide (DMSO)and the resulting mixture was heated at 85° C. for 6 h. The reactionmixture was then cooled to room temperature and extracted with asaturated aqueous sodium bicarbonate solution. The organic layer wasdried, concentrated, and purified using column chromatography to providecompound 1b as a yellow liquid.

Compounds 1c-k were made from compound 1b according to the followingprocedures:

1c: To compound 1b (440 mg, 2.22 mmol) dissolved in 3 ml of DMF wasadded 1.0 eq. (0.17 ml, 0.32 g, 2.22 mmol) of the phenethyl isocyanate.The resulting reaction mixture was placed on a shaker at roomtemperature. The reaction was monitored by liquid chromatography—massspectrmetry) LC/MS. After 30 min, the reaction product was isolated andpurified using column chromatography (ethyl acetate/hexane) to provide0.11 g of compound 1c.

1d: To compound 1b (110.0 mg, 0.56 mmol) dissolved in 3 ml of methylenechloride was added 1.1 eq. (0.10 ml, 0.10 g, 0.61 mmol) of4-i-propylphenyl isocyanate. The resulting reaction mixture was placedon a shaker at room temperature. The reaction was monitored by LC/MS.After 30 min, the reaction product was isolated and purified usingcolumn chromatography (ethyl acetate/hexane) to provide 0.19 g (92%) ofcompound 1d as white solid.

1e: To compound 1b (440 mg, 2.22 mmol) dissolved in 3 ml of DMF wasadded 1.0 eq. (0.11 ml, 0.39 g, 2.22 mmol) of 4-n-butylphenylisocyanate. The resulting reaction mixture was placed on a shaker atroom temperature. The reaction was monitored by LC/MS. After 30 min, thereaction product was isolated and purified using column chromatography(ethyl acetate/hexane) to provide 21.9 mg of compound 1e.

1f: To compound 1b (127.6 mg, 0.65 mmol) dissolved in 3 ml of methylenechloride was added 1.1 eq. (0.12 ml, 0.12 g, 0.72 mmol) of4-t-butylphenyl isocyanate. The resulting reaction mixture was placed ona shaker at room temperature. The reaction was monitored by LC/MS. After30 min, the reaction product was isolated and purified using columnchromatography (ethyl acetate/hexane) to provide 0.23 g (93%) ofcompound 1f as white solid.

1g: To compound 1b (201 mg, 1.02 mmol) dissolved in 3 ml of methylenechloride was added 1.0 eq. (260 mg, 1.02 mmol) of3,5-di-trifluoromethylphenyl isocyanate. The resulting reaction mixturewas placed on a shaker at room temperature. The reaction was monitoredby LC/MS. After 30 min, the reaction product was isolated and purifiedusing column chromatography (ethyl acetate/hexane) to provide 236.4 mgof compound 1g.

1h: To compound 1b (201 mg, 1.02 mmol) dissolved in 3 ml of methylenechloride was added 1.0 eq. (167 mg, 1.02 mmol) of 4-nitrophenylisocyanate. The resulting reaction mixture was placed on a shaker atroom temperature. The reaction was monitored by LC/MS. After 30 min, thereaction product was isolated and purified using column chromatography(ethyl acetate/hexane) to provide 18.9 mg of compound 1h.

1i: To compound 1b (201 mg, 1.02 mmol) dissolved in 3 ml of methylenechloride was added 1.0 eq. (203 mg, 1.02 mmol) of 2-chloro-4-nitrophenylisocyanate. The resulting reaction mixture was placed on a shaker atroom temperature. The reaction was monitored by LC/MS. After 30 min, thereaction product was isolated and purified using column chromatography(ethyl acetate/hexane) to provide 155.7 mg of compound 1i.

1j: To compound 1b (112 mg, 0.57 mmol) dissolved in 3 ml of methylenechloride was added 1.5 eq. (170 mg, 0.85 mmol) of4-cyclohexylphenylisocyanate. The resulting reaction mixture was placedon a shaker at room temperature. The reaction was monitored by LC/MS.After 30 min, the reaction product was isolated and purified usingcolumn chromatography (EtOAc/Hexane) to provide 202.2 mg of compound 1j.

1k: 2,3-dichloropyridine 1a (22 mg, 0.14 mmol) dissolved in 2 ml of DMSOwas added 1.1 eq. (14 mg, 0.16 mmol) of piperazine. The resultingreaction mixture was placed on a shaker at 85° C. for 4 h, cooled toroom temperature, 1.5 eq. (40 mg, 0.21 mmol) of 4-tert-butylbenzylisocyanate added, and the mixture placed on a shaker at room temperaturefor 1 h. The crude product was isolated and purified using columnchromatography by column chromatography (EtOAc/Hexane) to provide 8.5 mgof compound 1k.

The identity of compounds 1c-1k was confirmed by ¹H NMR.

1c: ¹H NMR (400 MHZ, CDCl₃): δ 8.18(dd, 1H, J=4.7, 1.6), 7.60(dd, 1H,J=7.8, 1.6), 7.36-7.18(m, 5H), 6.87(dd, 1H, J=7.8, 4.7), 4.48(bs, 1H),3.55-3.50(m, 2H), 3.48-3.45 (m, 4H), 3.34-3.33 (m, 4H), 2.85 (t, 2H,J=7.1).

1d: ¹H NMR (400 MHZ, CDCl₃): δ 8.20 (bd, 1H, J=4.6), 7.62 (d, 1H,J=7.7), 7.29 (d, 2H J=8.4), 7.15 (d, 2H J=8.4), 6.87 (dd, 1H J=7.7,4.8), 6.58 (bs, 1H), 3.67-3.64 (m, 4H), 3.41-3.39 (m, 4H), 2.91-2.84 (m,1H), 1.23 (d, 6H, J=6.9).

1e: ¹H NMR (400 MHZ, CDCl₃): δ 8.19(dd, 1H, J=4.7, 1.5), 7.61 (dd, 1H,J=7.7, 1.5), 7.25 (d, 2H, J=8.4), 7.10 (d, 2H, J=8.4), 6.89 (dd, 1H,J=7.7, 4.7), 6.34 (s, 1H), 3.67-3.64 (m, 2H), 3.42-3.40 (m, 4H), 2.58(t, 2H, J=7.6), 1.56 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H, J=7.3).

1f: ¹H NMR (400 MHZ, CDCl₃): δ 8.25 (dd, 1H, J=4.8, 1.6), 7.67 (dd, 1H,J=7.7, 1.6), 7.39-7.32 (m, 4H), 6.95 (dd, 1H, J=7.7, 4.7), 6.41 (bs,1H), 3.73-3.70 (m, 4H), 3.49-3.46 (m, 4H), 1.36 (s, 9H).

1g: ¹H NMR (400 MHZ, CDCl₃): δ 8.26 (dd, 1H, J=4.7, 1.6), 7.97 (s, 2H),7.70 (dd, 1H, J=7.8, J=1.6), 7.59(s, 1H), 6.97(dd, 1H, J=7.8, 4.8),6.76(s, 1H), 3.77-3.74(m, 4H), 3.51-3.48 (m, 4H).

1h: ¹H NMR (400 MHZ, CDCl₃): δ 8.27-8.24 (m, 3H), 7.70 (dd, 1H, J=7.8,J=1.6), 7.62 (dd, 2H, J=7.2, 2.0), 6.97 (dd, 1H, J=7.8, 4.7), 6.80 (bs,1H), 3.78-3.75 (m, 4H), 3.52-3.49 (m, 4H).

1i: ¹H NMR (400 MHZ, CDCl₃): δ 8.58(d, 1H, J=9.3), 8.36(d, 1H, J=2.5),8.27 (dd, 1H, J=4.8, 1.7), 7.70 (dd, 1H, J=7.8, 1.6), 7.48 (bs, 1H),6.98 (dd, 1H, J=7.8, 4.8), 3.82-3.79 (m, 4H), 3.54-3.52 (m, 4H).

1j: ¹H NMR (400 MHZ, CDCl₃): δ 8.26 (dd, 1H, J=4.7, 1.6), 7.68 (dd, 1H,J=7.8, 1.6), 7.34 (bd, 2H J=8.4), 7.21 (bd, 2H J=8.4), 6.94 (dd, 1H,J=7.7, 4.7), 6.37(bs, 1H), 3.73-3.70 (m, 4H), 3.49-3.47 (m, 4H), 2.51(m, 1H), 1.89 (m, 4H), 1.8 (m, 1H), 1.48-1.41 (m, 4H).

1k: ¹H NMR (400 MHZ, CDCl₃): δ 8.24 (dd, 1H, J=4.8, 1.7), 7.66 (dd, 1H,J=7.8, 1.7), 7.45-7.34 (m, 4H), 6.93 (dd, 1H, J=7.8, 4.8), 4.78 (t, 1H,J=5.0), 4.48 (d, 2H, J=5.3), 3.62-3.59 (m, 4H), 3.43-3.40 (m, 4H), 1.37(s, 9H).

5.2 Example 2 Synthesis of Compounds 2a and 2b

Compounds 2a and 2b were prepared from compound 1b (prepared as inExample 1) according to the following procedures:

2a: Compound 1b (440 mg, 2.22 mmol) was dissolved in 3 mL ofdimethylformamide, 1 eq. (0.42 g, 2.22 mmol) of 4-tert-butylphenylisothiocyanate was added to the solution, and the resulting reactionmixture placed on a shaker at room temperature. The reaction wasmonitored using LC/MS. After 30 min. the reaction product was isolatedand purified using column chromatography (ethyl acetate/hexane) toprovide 75.6 mg of 2a as a white solid.

2b: Compound 1b (440 mg, 2.22 mmol) was dissolved in 3 mL ofdimethylformamide, 1 eq. (0.39 g, 2.22 mmol) of4-isopropylphenylisothiocyanate was added to the solution, and theresulting reaction mixture placed on a shaker at room temperature. Thereaction was monitored using LC/MS. After 30 min. the reaction productwas isolated and purified using column chromatography (ethylacetate/hexane) to provide 28.6 mg of 2a as a white solid.

The identity of compounds 2a and 2b was confirmed by ¹H NMR.

2a: ¹H NMR (400 MHZ, CDCl₃): δ 8.18 (dd, 1H, J=4.7, 1.6), 7.60 (dd, 1H,J=7.8, 1.6), 7.35(d, 2H, J=8.5), 7.20(s, 1H), 7.10(d, 2H, J=8.5), 6.88(dd, 1H, J=7.8, 4.7), 4.00-3.98 (m, 4H), 3.47-3.44 (m, 4H), 1.31 (s,9H).

2b: ¹H NMR (400 MHZ, CDCl₃): δ 8.18 (dd, 1H, J=4.7, 1.6), 7.60 (dd, 1H,J=7.8, 1.6), 7.20 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.4), 6.88 (dd, 1H,J=7.8, 4.7), 4.00-3.98 (m, 4H), 3.47-3.44 (m, 4H), 2.93-2.86 (m, 1H),1.24 (d, 6H, J=6.9).

5.3 Example 3 Synthesis of Compounds 3a-3b

Compounds 3a and 3b were prepared by the following procedures:

3a: To compound 3q (0.25 g, 1.07 mmol) dissolved in 3 ml of DMSO wasadded 1.1 eq. (0.1 g, 1.17 mmol) of piperazine and the resultingreaction mixture placed on a shaker at 85° C. for 4 h. After 4 h, thereaction mixture was cooled to room temperature, 1.1 eq. (0.21 g, 1.17mmol) of 4-t-butyl-phenyl isocyanate added, and the mixture placed on ashaker at room temperature for 1 h. The reaction product was thenisolated and purified using column chromatography (ethyl acetate/hexane)to provide 91.2 mg of 3a as a white solid.

3b: To compound 3r (24 mg, 0.097 mmol) dissolved in 3 ml of DMSO wasadded 1.2 eq. (11 mg, 0.12 mmol) of piperazine and the resultingreaction mixture placed on a shaker at 85° C. for 4 h. After 4 h, thereaction mixture was cooled to room temperature, 1.0 eq. (17 mg, 0.097mmol) of 4-t-butyl-phenyl isocyanate added, and the mixture placed on ashaker at room temperature for 1 h. The reaction product was thenisolated and purified using column chromatography (ethyl acetate/hexane)to provide 20.3 mg of compound 3b.

The identity of compounds 3a and 3b was confirmed by ¹H NMR.

3a: ¹H NMR (400 MHZ, CDCl₃): δ 8.27 (dd, 1H, J=4.7, 1.6), 7.84 (dd, 1H,J=7.8, 1.6), 7.35-7.29 (m, 4H), 6.85 (dd, 1H, J=7.8, 4.7), 6.35 (bs,1H), 3.70-3.67 (m, 4H), 3.42-3.40 (m, 4H), 1.32 (s, 9H).

3b: ¹H NMR (400 MHZ, CDCl₃): δ 8.34 (dd, 1H, J=4.7, 1.7), 8.15 (dd, 1H,J=7.7, 1.7), 7.39-7.33 (m, 4H), 6.76 (dd, 1H, J=7.7, 4.7), 6.40 (s, 1H),3.75-3.72 (m, 4H), 3.40-3.37 (m, 4H), 1.36 (s, 9H).

5.4 Example 4 Synthesis of Compounds 4a-4b

Compounds 4a and 4b were prepared by the following procedures:

4a: To compound 4n (0.24 g, 1.01 mmol) dissolved in 3 ml of DMSO wasadded 1.1 eq. (0.096 g, 1.11 mmol) of piperazine and the resultingreaction mixture placed on a shaker at 85° C. for 4 h. After 4 h, thereaction mixture was cooled to room temperature, 1.1 eq. (0.18 ml, 0.18g, 1.11 mmol) of 4-i-propyl-phenyl isocyanate added, and the mixtureplaced on a shaker at room temperature for 1 h. The reaction product wasthen isolated and purified using column chromatography (ethylacetate/hexane) to provide 56.2 mg of compound 4a as a white solid.

4b: To compound 4o (24 mg, 0.097 mmol) dissolved in 3 ml of DMSO wasadded 1.2 eq. (11 mg, 0.12 mmol) of piperazine and the resultingreaction mixture placed on a shaker at 85° C. for 4 h. After 4 h, thereaction mixture was cooled to room temperature, 1.0 eq. (16 mg, 0.097mmol) of 4-i-propyl-phenyl isocyanate added, and the mixture placed on ashaker at room temperature for 1 h. The reaction product was thenisolated and purified using column chromatography (ethyl acetate/hexane)to provide 19.6 mg of compound 3b.

The identity of compounds 4a and 4b was confirmed by ¹H NMR.

4a: ¹H NMR (400 MHZ, CDCl₃): δ 8.34 (dd, 1H, J=4.7, 1.6), 8.15 (dd, 1H,J=7.7, 1.6), 7.34(d, 2H J=8.5), 7.21 (d, 2H J=8.5), 6.76(dd, 1H J=7.7,4.7), 6.41 (s, 1H), 3.75-3.72 (m, 4H), 3.39-3.36 (m, 4H), 2.94-2.91 (m,1H), 1.28 (d, 6H, J=6.9).

4b: ¹H NMR (400 MHZ, CDCl₃): δ 8.31 (d, 1H, J=4.8), 7.27 (bd, 2H,J−==8.5), 7.13 (d, 2H. J=8.5), 6.51 (t, 1H, J=4.7), 3.86-3.83 (m, 4H),3.56-3.53 (m, 4H), 2.85-2.82 (m, 1H), 1.20 (d, 6H, J=6.9).

5.5 Example 5 Synthesis of Compound 5a

To 50 mL of a DMSO solution of compound 5b (1 g) was added2,5-dimethylpiperazine (3 eq) followed by the addition ofdi-isopropylethyl amine (DIEA) (0.87 g). The reaction mixture wasstirred at 120° C. for 15 hours. Water and ethyl acetate were added tothe reaction mixture, and the organic and aqueous phases were separated.The aqueous phase was extracted twice with ethyl acetate. The organicextracts were combined, washed with water, washed with brine, dried withsodium sulfate, and concentrated to provide compound 5c (0.44 g).Compound 5c (0.44 g) was reacted with 4-i-propyl-phenyl isocyanate (1.2eq) in DCM (2 mL) to provide compound 5a (0.028 g). Compound 5a waspurified using silica-gel chromatography (30:70 ethyl acetate:hexane).The identity of compound 5a was confirmed using ¹H NMR.

5a: ¹H NMR (400 MHZ, CD₃OD): δ 1.24 (d, 3H), 1.29 (d, 6H), 2.23 (d, 3H),2.85 (m, 1H), 3.40 (d, 1H), 3.71 (q, 3H), 4.45 (bs, 2H), 6.45 (s, 1H),6.75 (m, 1H), 7.12 (m, 2H), 7.25 (m, 2H), 7.51 (dd, 1H), 8.12 (m, 1H).

5.6 Example 6 Synthesis of Compounds 6a-6e

To compound 6d (2 g) in 25 mL of dimethylsulfoxide (DMSO) was addedpiperazine (3.46 g) followed by the addition of DIEA (1.76 g). Thereaction mixture was stirred at 120° C. for 15 hours. Water and ethylacetate were added to the reaction mixture, and the organic and aqueousphases were separated. The aqueous phase was extracted twice with ethylacetate. The organic extracts were combined, washed with water, washedwith brine, dried with sodium sulfate, and concentrated to providecompound 6f (1.3 g). Compound 6f (0.2 g) was reacted with theappropriate isocyanate, RNCO, (0.047 g of 4-bromophenyl isocyante forcompound 6a, 0.53 g of 4-iodoophenyl isocyante for compound 6b, 0.43 gof 4-acetylphenyl isocyante for compound 6c, 0.50 g of 4-benzyloxyphenylisocyante for compound 6d, and 0.16 g of 4-n-propylphenyl isocyante forcompound 6e) in 5 mL of DCM to provide compounds 6a-e. The identity ofcompounds 6a-e was confirmed using ¹H NMR.

6a: ¹H NMR (400 MHZ, DMSO): δ 3.25 (bs, 4H), 3.75 (bs, 4H), 7.01 (m,1H), 7.45 (d, 2H), 7.52 (d, 2H), 7.92 (dd, 1H), 8.22 (dd, 1H), 8.82 (s,1H).

6b: ¹H NMR (400 MHZ, DMSO): δ 3.25 (bs, 4H), 3.75 (bs, 4H), 7.01 (m,1H), 7.45 (d, 2H), 7.52 (d, 2H), 7.92 (dd, 1H), 8.22 (dd, 1H), 8.82 (s,1H).

6c: ¹H NMR (400 MHZ, DMSO): δ 2.25 (s, 3H), 3.35 (bs, 4H), 3.75 (bs,4H), 7.01 (m, 1H), 7.55 (d, 2H), 7.82 (d, 2H), 8.27 (dd, 1H), 9.05 (dd,1H), 9.47 (s, 1H).

6d: ¹H NMR (400 MHZ, DMSO): 3.35 (bs, 4H), 3.75 (bs, 4H), 5.01 (s, 2H),6.90 (m, H), 7.02 (m, 1H), 7.45-7.55 (bm, 7H), 7.77 (dd, 1H), 8.25 (dd,1H), 8.40 (s, 1H).

6e: ¹H NMR (400 MHZ, DMSO): 0.91 (m, 3H), 1.52 (m, 2H), 2.50 (q, 2H),3.25 (t, H), 3.62 (t, 4H), 6.45 (s, 1H), 6.82 (dd, 1H), 7.15 (t, 2H),7.25 (t, 2H), 7.78 (dd, 1H), 8.25 dd, 1H).

5.7 Example 7 Synthesis of Compounds 7a-7i

To 5 g (43.65 mmol) of 2-fluoro-3-methylpyridine in 20 mL of DMSO wasadded 20 g (˜5.3 eq.) of piperazine, and the resulting mixture washeated to reflux (˜130° C.) overnight under a drying tube. The reactionmixture was cooled, diluted with 50 mL of H₂O, and extracted with ethylacetate (3×40 mL). The organic phase was washed with H₂O, aqueoussaturated NaCl, and dried over MgSO₄. The organic solvent was thenremoved under reduced pressure, and the resulting residue was dissolvedin minimum amount of CH₂Cl₂ and purified using silica-gel chromatography(elution: varied ratios of ethyl acetate/hexane to ethyl acetate/MeOH)to provide 2.2 g (yield: 28.4%) of 7j as a pale yellow oil. The identityof compounds 7j was confirmed by ¹H NMR. chromatography.

7j: ¹H NMR (400 MHz, CDCl₃) δ 1.70 (broad s, 1), 2.29 (s, 3), 3.03 (t,4), 3.11 (t, 4), 6.85 (dd, 1), 7.40 (d, 1), 8.18 (d, 1).

Other Piperazine Compounds can be prepared using other appropriatelysubstituted 2-fluoropyridines according to Scheme H:

To a solution of 0.239 g (1.3472 mmol) of 3-methyl-2-piperazinylpyridine(7j) in 10 mL of CH₂Cl₂ was added 0.236 g (1 eq.) of 4-tert-butylphenylisocyanate. The mixture was stirred under N₂ overnight. The solvent wasthen removed under reduced pressure and the resulting residue wasrecrystallized from ethyl acetate-hexane to provide 0.34 g (yield:71.6%) of 7a as white crystals (see Scheme I wherein R₁=3-CH₃, R₂═H,Y═O, and R₅=4-tert-butylphenyl).

Compounds 7b-f were made using a procedure analogous to that used tomake compound 7a, but using the appropriate isocyanate. The structure ofcompounds 7a-f is provided in Table I below. TABLE I Compounds 7a-f. R₁R₂ R₅ Y Product 3-Me H 4-tert-butylphenyl O

3-Me H 4-isopropylphenyl O

3-Me H 4-butylphenyl O

3-Cl H 4-tert-butylcyclohexyl O

3-Cl H cyclooctyl S

3-Cl H (4-ethyl carboxylate)phenyl O

The identity of compounds 7a-f was confirmed by ¹H NMR.

7a: ¹H NMR (400 MHz, CDCl₃) δ 1.26 (s, 9), 2.30 (s, 3), 3.20 (t, 4),3.64 (t, 4), 6.41 (broad s, 1), 6.89 (t, 1), 7.30 (m, 4), 7.42 (d, 1),8.16 (d, 1).

7b: ¹H NMR (400 MHz, CDCl₃) δ 1.21 (d, 6), 2.29 (s, 3), 2.83 (m, 1),3.17 (t, 4), 3.62 (t, 4), 6.62 (broad s, 1), 6.88 (dd, 1), 7.14 (d, 2),7.27 (d, 2), 7.42 (dd, 1), 8.12 (dd, 1).

7c: ¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, 3), 1.31 (m, 2), 1.53 (m, 2),2.28 (s, 3), 2.53 (t, 3), 3.15 (t, 4), 3.60 (t, 4), 6.76 (s, 1), 6.88(dd, 1), 7.07 (d, 2), 7.27 (d, 2), 7.42 (d, 1), 8.15 (d, 1).

7d: ¹H NMR (400 MHz, CDCl₃) δ 0.85 (s, 9), 0.96 (m, 1), 1.12 (m, 4),1.79 (t, 2), 2.06 (t, 2), 3.28 (t, 4), 3.50 (t, 4), 3.60 (m, 1), 4.34(d, 1), 7.02 (dd, 1), 7.87 (d, 1), 8.43 (d, 1).

7e: ¹H NMR (400 MHz, CDCl₃) δ 1.70 (m, 12), 2.06 (m, 2), 3.54 (t, 4),4.04 (t, 4), 4.73 (m, 1), 5.65 (d, 1), 6.97 (dd, 1), 7.71 (d, 1), 8.26(d, 1).

7f: ¹H NMR (400 MHz, CDCl₃) δ 1.38 (t, 3), 3.41 (t, 4), 3.68 (t, 4),4.32 (quartet, 2), 6.89 (m, 1), 6.96 (broad s, 1), 7.48 (dd, 2), 7.63(d, 1), 7.97 (d, 2), 8.19 (d, 1).

5.8 Example 8 Binding of the Piperazine Compounds to the Human VR1Receptor

VR1 antagonism has been associated with the prevention of pain (See,e.g., R. Wrigglesworth and C. Walpole, “Capsaicin-like Agonists,” Drugsof the Future, 23(5), pp. 531-538 (1998); S. Bevan P. McIntyre,“Vanilloid Receptors: Pivotal Molecules in Nocciception,” CurrentOpinions in CPNS Investigational Drugs, vol. 2, no. 2, pp. 178-185(2000) and A. Szallash and P. Blumberg, “Vanilloid (Capsaicin) Receptorsand Mechanisma,” Pharmacology Reviews, vol. 51, no. 2, pp. 159-211(1999)).

Methods for assaying compounds capable of inhibiting VR1 are well knownto those skilled in the art, for example, those methods disclosed inU.S. Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 toMcIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al.

Typically, the Piperazine Compounds have an IC₅₀ value for inhibition ofcapsaicin-induced activation that is less than 25 μM, preferably lessthan 1,000 nM, and more preferably less than 500 nM, or an IC₅₀ valuefor inhibition of pH-induced inactivation that is less than 10 μM,preferably less than 1,000 nM, and more preferably less than 500 nM.

The following Piperazine Compound inhibits capsaicin-induced activationand pH-induced activation of VR1 as shown below: Inhibition ofCapsaicin- Inhibition of pH-Induced Induced Activation Activation IC₅₀(nM) IC₅₀ (nM) Compound Mean IC₅₀ ± SEM^(a) (n)^(b) Mean IC₅₀ ± SEM^(a)(n)^(b)

1.3 ± 1.2 (3) 5.4 ± 2.5 (3)^(a)SEM = standard deviation^(b)n = number of experiments

5.9. Example 9 Binding of Piperazine Compounds to mGluR5

The following astrocyte assay can be used to demonstrate that PiperazineCompounds bind to and modulate the activity of mGluR5.

Cell cultures: Primary glial cultures are prepared from cortices ofSprague-Dawley 18 days old embryos. The cortices are dissected and thendissociated by trituration. The resulting cell homogenate is plated ontopoly-D-lysine precoated T175 flasks (BIOCOAT, commercially availablefrom Becton Dickinson and Company Inc. of Franklin Lakes, N.J.) inDulbelcco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25mM HEPES, and supplemented with 15% fetal calf serum (“FCS,”commercially available from Hyclone Laboratories Inc. of Omaha, Nebr.),and incubated at 37° C. and 5% CO₂. After 24 hours, FCS supplementationis reduced to 10%. On day six, oligodendrocytes and microglia areremoved by strongly tapping the sides of the flasks. One day followingthis purification step, secondary astrocyte cultures are established bysubplating onto 96 poly-D-lysine precoated T175 flasks BIOCOAT) at adensity of 65,000 cells/well in DMEM and 10% FCS. After 24 hours, thestrocytes are washed with serum free medium and then cultured in DMEM,without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mLepidermal growth factor (“EGF”), 1 mM sodium pyruvate, and 1×penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO₂.The procedure allows the expression of the mGluR5 receptor byastrocytes, as demonstrated by S. Miller et al., J. Neuroscience15(9):6103-6109 (1995).

Assay Protocol: After 3-5 days incubation with EGF, the astrocytes arewashed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mM NaH₂PO₄, 2 mMCaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM Glucose at pH 7.4 (“Assay Buffer”)and loaded with the dye Fluo-4 (commercially available from MolecularProbes Inc. of Eugene, Oreg.) using 0.1 mL of Assay Buffer containingFluo-4 (3 mM final). After 90 minutes of dye loading, the cells are thenwashed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of AssayBuffer. The plates containing the astrocytes are then transferred to aFluorometric Imaging Plate reader (commercially available from MolecularDevices Corporation of Sunnyvale, Calif.) for the assessment of calciummobilization flux in the presence of glutamate and in the presence orabsence of antagonist. After monitoring fluorescence for 15 seconds toestablish a base line, DMSO solutions containing various concentrationsof a Piperazine Compound diluted in Assay Buffer (0.05 mL of 4×dilutions for competition curves) are added to the cell plate andfluorescence is monitored for 2 minutes. 0.05 mL of a 4× glutamatesolution (agonist) is then added to each well to provide a finalglutamate concentration in each well of 10 mM. Plate fluorescence isthen monitored for an additional 60 seconds after agonist addition. Thefinal DMSO concentration in the assay is 1.0%. In each experiment,fluorescence is monitored as a function of time and the data analyzedusing Microsoft Excel and GraphPad Prism. Dose-response curves are fitusing a non-linear regression to determine IC₅₀ value. In eachexperiment, each data point is determined two times. The resultsdemonstrate Piperazine Compounds that bind to and modulate the activityof mGluR5.

The following CHO assay can be used to demonstrate that PiperazineCompounds bind to and modulate the activity of mGluR5.

40,000 CHO-rat mGluR5 cells/well were plated into 96 well plate (Costar3409, Black, clear bottom, 96 well, tissue culture treated) for anovernight incubation in Dulbelcco's Modified Eagle's Medium (DMEM, pH7.4) and supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500ug/ml Geneticin. CHO-rat mGluR5 cells were washed and treated withOptimem medium and incubated for 1-4 hours prior to loading cells. Cellplates were then washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mMMgC₂, 700 μM Na H₂PO₄, 2 mM CaCl₂, 5 mM Na HCO₃, 8 mM Hepes, and 10 mMGlucose, pH 7.4) and then incubated with 3 μM Fluo 4 (commerciallyavailable from Molecular probes Inc. of Eugene, Oreg.) in 0.1 mL ofloading buffer. After 90 minutes of dye loading, the cells were thenwashed twice with 0.2 mL loading buffer and resuspended in 0.1 mLloading buffer. The plates containing the CHO-rat mGluR5 cells were thentransferred to Fluorometric Imaging Plate Reader (FLIPR) (commerciallyavailable from Molecular Devices Corporation of Sunnyvale, Calif.) forthe assessment of calcium mobilization flux in the presence of glutamateand in the presence or absence of test compounds. After monitoringfluorescence for 15 seconds to establish a base line, DMSO solutionscontaining various concentrations of the test compound diluted inloading buffer (0.05 nL of 4× dilutions for the competition curves) wereadded to the cell plate and fluorescence was monitored for 2 minutes.0.05 mL of 4× glutamate solution (agonist) was then added to each wellto provide a final glutamate concentration in each well of 10 uM. Platefluorescence is then monitored for an additional 60 seconds afteragonist addition. The final DMSO concentration in the assay was 1.0%. Ineach experiment, fluorescence is monitored as a function of time and thedata analyzed using Microsoft Excel and GraphPad Prism. Dose-responsecurves were fit using a non-linear regression to determine IC50 value.In each experiment each data point was determined two times.

Using the above CHO assay, the following compound inhibits mGluR5 at aconcentration of 10 μM:

5.10. Example 10 In Vivo Assays for Prevention or Treatment of Pain

Test Animals: Each experiment uses rats weighing between 200-260 g atthe start of the experiment. The rats are group-housed and have freeaccess to food and water at all times, except prior to oraladministration of a Piperazine Compound when food is removed for 16hours before dosing. A control group acts as a comparison to ratstreated with a Piperazine Compound. The control group is administeredthe carrier for the Piperazine Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Piperazine Compound administered to the test group.

Acute Pain: To assess the actions of the Piperazine Compounds for thetreatment or prevention of acute pain the rat tail flick test can beused. Rats are placed inside a cotton pouch and the tail exposed to afocused beam of radiant heat at a point 3 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 15 seconds are removed from the tail flick unit andassigned a withdrawal latency of 15 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 6 hoursfollowing administration of a Piperazine Compound. Data are expressed astail flick latency(s) and the percentage of the maximal possible effect(% MPE), i.e., 15 seconds, is calculated as follows:${\%\quad{MPE}} = {\frac{\left\lbrack {\left( {{post}\quad{administration}\quad{latency}} \right) - \left( {{pre}\text{-}{administration}\quad{latency}} \right)} \right\rbrack}{\left( {15\quad s\quad{pre}\text{-}{administration}\quad{latency}} \right)} \times 100}$The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941). The results demonstrate Piperazine Compounds that areuseful for treating or preventing acute pain.

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(PWT), as described below.

Inflammatory Pain: To assess the actions of the Piperazine Compounds forthe treatment or prevention of inflammatory pain the Freund's completeadjuvant (FCA) model of inflammatory pain is used. FCA-inducedinflammation of the rat hind paw is associated with the development ofpersistent inflammatory mechanical hyperalgesia and provides reliableprediction of the anti-hyperalgesic action of clinically usefulanalgesic drugs (L. Bartho et al., “Involvement of Capsaicin-sensitiveNeurones in Hyperalgesia and Enhanced Opioid Antinociception inInflammation,” Naunyn-Schmiedeberg's Archives of Pharmacology342:666-670 (1990)). The left hind paw of each animal is administered a50 μL intraplantar injection of 100% FCA. 24 hour post injection, theanimal is assessed for response to noxious mechanical stimuli bydetermining the PWT, as described below. Rats are then administered asingle injection of 1, 3, 10 or 30 mg/Kg of either a PiperazineCompound, 30 mg/Kg indomethacin or carrier. Responses to noxiousmechanical stimuli are then determined 2, 4, 6, and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:${\%\quad{Reversal}} = {\frac{\left\lbrack {\left( {{post}\quad{administration}\quad{PWT}} \right) - \left( {{pre}\text{-}{administration}\quad{PWT}} \right)} \right\rbrack}{\left( {{Baseline}\quad{pre}\text{-}{administration}\quad{PWT}} \right)} \times 100}$The results demonstrate Piperazine Compounds that are useful fortreating or preventing inflammatory pain.

Neuropathic Pain: To assess the actions of the Piperazine Compounds forthe treatment or prevention of neuropathic pain either the Seltzer modelor the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underenflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the conunon sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (7-0 silk) anda Michelle clip. Following surgery, the wound area is dusted withantibiotic powder. Sham-treated rats undergo an identical surgicalprocedure except that the sciatic nerve is not manipulated. Followingsurgery, animals are weighed and placed on a warm pad until they recoverfrom anesthesia. Animals are then returned to their home cages untilbehavioral testing begins. The animal is assessed for response tonoxious mechanical stimuli by determining PWT, as described below,immediately prior to and 1, 3, and 6 hours after drug administration forboth the left rear paw and right rear paw of the animal. Percentagereversal of neuropathic hyperalgesia is defined as:% reversal=100−[(right pre-administration PWT−left post-administrationPWT)/(right pre-administration PWT−left pre-administration PWT)]×100.

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, themal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then be returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, immediately prior to and 1, 3, and 5 hours afterbeing administered a Piperazine Compound for both the left rear paw andright rear paw of the animal. The animal can also be assessed forresponse to noxious thermal stimuli or for tactile allodynia, asdescribed below. The Chung model for neuropathic pain is described in S.H. Kim, “An Experimental Model for Peripheral Neuropathy Produced bySegmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).The results show demonstrate Piperazine Compounds that are useful fortreating or preventing neuropathic pain.

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacology Biochemistry and Behavior 31:451-455 (1988).The maximum weight that can be applied to the hind paw is set at 250 gand the end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Only theaffected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

5.11. Example 11 In Vivo Assays for Prevention or Treatment of Anxiety

The elevated plus maze test or the shock-probe burying test can be usedto assess the anxiolytic activity of Piperazine Compounds in rats ormice.

The Elevated Plus Maze Test: The elevated plus maze consists of aplatform with 4 arms, two open and two closed (50×10×50 cm enclosed withan open roof). Rats (or mice) are placed in the center of the platform,at the crossroad of the 4 arms, facing one of the closed arms. Timespent in the open arms vs the closed arms and number of open arm entriesduring the testing period are recorded. This test is conducted prior todrug administration and again after drug administration. Test resultsare expressed as the mean time spent in open arms and the mean number ofentries into open arms. Known anxiolytic drugs increase both the timespent in open arms and number of open arm entries. The elevated plusmaze test is described in D. Treit, “Animal Models for the Study ofAnti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews9(2):203-222 (1985).

The Shock-Probe Burying Test: For the shock-probe burying test thetesting apparatus consists of a plexiglass box measuring 40×30×40 cm,evenly covered with approximately 5 cm of bedding material (odorabsorbent kitty litter) with a small hole in one end through which ashock probe (6.5 cm long and 0.5 cm in diameter) is inserted. Theplexiglass shock probe is helically wrapped with two copper wiresthrough which an electric current is administered. The current is set at2 mA. Rats are habituated to the testing apparatus for 30 min on 4consecutive days without the shock probe in the box. On test day, ratsare placed in one corner of the test chamber following drugadministration. The probe is not electrified until the rat touches itwith its snout or fore paws, at which point the rat receives a brief 2mA shock. The 15 min testing period begins once the rat receives itsfirst shock and the probe remains electrified for the remainder of thetesting period. The shock elicits burying behavior by the rat. Followingthe first shock, the duration of time the rat spends spraying beddingmaterial toward or over the probe with its snout or fore paws (buryingbehavior) is measured as well as the number of contact-induced shocksthe rat receives from the probe. Known anxiolytic drugs reduce theamount of burying behavior. In addition, an index of the rat'sreactivity to each shock is scored on a 4 point scale. The total timespent immobile during the 15 min testing period is used as an index ofgeneral activity. The shock-probe burying test is described in D. Treit,1985, supra. The results demonstrate Piperazine Compounds that areuseful for treating or preventing anxiety.

5.12. Example 12 In Vivo Assays for Prevention or Treatment of anAddictive Disorder

The condition place preference test or drug self-administration test canbe used to assess the ability of Piperazine Compounds to attenuate therewarding properties of known drugs of abuse.

The Condition Place Preference Test: The apparatus for the conditionedplace preference test consists of two large compartments (45×45×30 cm)made of wood with a plexiglass front wall. These two large compartmentsare distinctly different. Doors at the back of each large compartmentlead to a smaller box (36×18×20 cm) box made of wood, painted grey, witha ceiling of wire mesh. The two large compartments differ in terms ofshading (white vs black), level of illumination (the plexiglass door ofthe white compartment is covered with aluminum foil except for a windowof 7×7 cm), texture (the white compartment has a 3 cm thick floor board(40×40 cm) with nine equally spaced 5 cm diameter holes and the blackhas a wire mesh floor), and olfactory cues (saline in the whitecompartment and 1 mL of 10% acetic acid in the black compartment). Onhabituation and testing days, the doors to the small box remain open,giving the rat free access to both large compartments.

The first session that a rat is placed in the apparatus is a habituationsession and entrances to the smaller grey compartment remain open givingthe rat free access to both large compartments. During habituation, ratsgenerally show no preference for either compartment. Followinghabituation, rats are given 6 conditioning sessions. Rats are dividedinto 4 groups: carrier pre-treatment+carrier (control group),2-Pyrimidinylpiperazine Compound pre-treatment+carrier, carrierpre-treatment+morphine, 2-Pyrimidinylpiperazine Compoundpre-treatment+morphine. During each conditioning session the rat isinjected with one of the drug combinations and confined to onecompartment for 30 min. On the following day, the rat receives acarrier+carrier treatment and is confined to the other largecompartment. Each rat receives three conditioning sessions consisting of3 drug combination-compartment and 3 carrier-compartment pairings. Theorder of injections and the drug/compartment pairings arecounterbalanced within groups. On the test day, rats are injected priorto testing (30 min to 1 hour) with either morphine or carrier and therat is placed in the apparatus, the doors to the grey compartment remainopen and the rat is allowed to explore the entire apparatus for 20 min.The time spent in each compartment is recorded. Known drugs of abuseincrease the time spent in the drug-paired compartment during thetesting session. If the Piperazine Compound blocks the acquisition ofmorphine conditioned place preference (reward), there will be nodifference in time spent in each side in rats pre-treated with aPiperazine Compound and the group will not be different from the groupof rats that was given carrier+carrier in both compartments. Data willbe analyzed as time spent in each compartment (drug combination-pairedvs carrier-paired). Generally, the experiment is repeated with a minimumof 3 doses of a Piperazine Compound.

The Drug Self-Administration Test: The apparatus for the drugself-administration test is a standard commercially available operantconditioning chamber. Before drug trials begin rats are trained to pressa lever for a food reward. After stable lever pressing behavior isacquired, rats are tested for acquisition of lever pressing for drugreward. Rats are implanted with chronically indwelling jugular cathetersfor i.v. administration of compounds and are allowed to recover for 7days before training begins. Experimental sessions are conducted dailyfor 5 days in 3 hour sessions. Rats are trained to self-administer aknown drug of abuse, such as morphine. Rats are then presented with twolevers, an “active” lever and an “inactive” lever. Pressing of theactive lever results in drug infusion on a fixed ratio 1 (FR1) schedule(i.e., one lever press gives an infusion) followed by a 20 second timeout period (signaled by illumination of a light above the levers).Pressing of the inactive lever results in infusion of excipient.Training continues until the total number of morphine infusionsstabilizes to within ±10% per session. Trained rats are then used toevaluate the effect of Piperazine Compounds pre-treatment on drugself-administration. On test day, rats are pre-treated with a PiperazineCompound or excipient and then are allowed to self-administer drug asusual. If the Piperazine Compound blocks the rewarding effects ofmorphine, rats pre-treated with the Piperazine Compound will show alower rate of responding compared to their previous rate of respondingand compared to excipient pre-treated rats. Data is analyzed as thechange in number of drug infusions per testing session (number ofinfusions during test session−number of infusions during trainingsession). The results show that Piperazine Compounds are useful fortreating or preventing an addictive disorder.

5.13. Example 13 Functional Assay for Characterizing mGluR 1Antagonistic Properties

Functional assays for the characterization of mGluR1 antagonisticproperties are well known in the art. For example, the followingprocedure can be used.

cDNA encoding rat mGluR1a receptor is obtained from, e.g., Prof. S.Nakanishi (Kyoto, Japan). It is transiently transfected into HEK-EBNAcells using a procedure described by Schlaeger et al., New Dev. NewAppl. Anim. Cell Techn., Proc. ESACT Meet., 15^(th) à (1998), 105-112and 117-120. [Ca²⁺] measurements are performed on mGluR1a transfectedHEK-EBNA cells after incubation of the cells with Fluo-3 AM (0.5 μMfinal concentration) for 1 hour at 37° C. followed by 4 washes withassay buffer (DMEM supplemented with Hank's salt and 20 mM HEPES).[Ca²⁺] measurements are done using a flurometric imaging plate reader,e.g., FLIPR from Molecular Devices Corporation, La Jolla, Calif. 10 μMglutamate as agonist is used to evaluate the potency of the antagonists.

Increasing concentrations of antagonists are applied to the cells 5minutes prior to application of the agonist. The inhibition(antagonists) curves are fitted with appropriate software, for example,the four-parameter logistic equation giving IC₅₀ and Hill coefficientusing the iterative nonlinear curve fitting software Origin fromMicrocal Software Inc., Northampton, Mass.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A method for treating or preventing pain in an animal, comprisingadministering to an animal in need thereof an effective amount of thecompound or a pharmaceutically acceptable salt of the compound offormula:

wherein: X is O or S; z is 0 or 1; when z is 0, R¹ is —CH₃ or -halo;when z is 1, R¹ is —H, -halo, —(C₁-C₆)alkyl, —NO₂, —CN, —OH, —OCH₃,—C(halo)₃, —CH(halo)₂, or —CH₂(halo); R² is: (a) —(C₂-C₆)alkyl,—(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, which isunsubstituted or substituted with one or more of —CN, —OH, -halo, —NO₂,—CH═NR⁶, or —NR⁶OH; (b) —CH₃, —CH₂F, or —CHF₂, which is unsubstituted orsubstituted with one or more of —CN, —OH, —Cl, —Br, —I, —NO₂, —CH═NR⁶,or —NR⁶OH; or (c) —H, -halo, —NO₂, —CN, or —NH₂; R³ is: (a)—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶, which isunsubstituted or substituted with one or more of —CN, —OH, -halo, —NO₂,—CH═NR , or —NR⁶OH; or (b) —H, -halo, —NO₂, —CN, or —NH₂; R⁴ is —H; Aris —(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₈)cycloalkyl or—(C₅-C₈)cycloalkenyl, which is unsubstituted or substituted with one ormore R⁷ groups; each R⁵ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, or —(CH₂)_(n)OR⁶; eachR⁶ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, or-aryl; each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, or —(CH₂)_(n)OR⁶; n isan integer ranging from 0 to 2; and p is an integer ranging from 0 to 2.2. The method of claim 1, further comprising administering an effectiveamount of an opioid analgesic.
 3. The method of claim 1, furthercomprising administering an effective amount of a non-opioid analgesic.4. The method of claim 1, further comprising administering an effectiveamount of an anti-emetic agent.
 5. A method for treating or preventingpain in an animal, comprising administering to an animal in need thereofan effective amount of the compound or a pharmaceutically acceptablesalt of the compound of formula:

wherein: X is O or S; R¹ is —CH₃ or -halo; R² is: (a) —(C₂-C₆)alkyl,—(C₂-C₃)alkenyl, —CH₃, —CH₂F, or —CHF₂, which is substituted with one ormore of —NO₂, —CH═NR⁶, or —NR⁶OH; or (b) —(CH₂)_(m)C(O)R⁶,—(CH₂)_(m)OR⁶, or —(CH₂)_(m)SR⁶, which is unsubstituted or substitutedwith one or more of —CN, —OH, -halo, —NO₂, —CH═NR⁶, or —NR⁶OH; R³ is:(a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(n)OR⁶,which is unsubstituted or substituted with one or more of —CN, —OH,-halo, —NO₂, —CH═NR⁶, or —NR⁶OH; or (b) —H, -halo, —NO₂, —CN, or —NH₂;R⁴ is —H; R⁵ is: (a) —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl; or (b)—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₆)aryl, —(C₁₀)aryl,—(C₁₄)aryl, —(C₃-C₇)heterocycle, —(C₁-C₆)alkyl(C₆)aryl,—(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups; each R⁶ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, —(C₆)aryl, —(C₃-C₅)heterocycle, —C(halo)₃, or—CH(halo)₂; each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, or —(CH₂)_(n)OR⁶; m is 1or 2; and n is an integer ranging from 0 to
 2. 6. The method of claim 5,further comprising administering an effective amount of an opioidanalgesic.
 7. The method of claim 5, further comprising administering aneffective amount of a non-opioid analgesic.
 8. The method of claim 5,further comprising administering an effective amount of an anti-emeticagent.
 9. A method for treating or preventing pain in an animal,comprising administering to an animal in need thereof an effectiveamount of the compound or a pharmaceutically acceptable salt of thecompound of formula:

wherein: X is O or S; R¹ is —CH₃ or -halo; R² is: (a) —(C₂-C₆)alkyl,—(C₂-C₃)alkenyl, —(CH₂)_(n)C(O)R⁶, —(CH₂)_(n)OR⁶, —(CH₂)_(n)SR⁶, whichis unsubstituted or substituted with one or more of —CN, —OH, -halo,—NO₂, —CH═NR⁶, or —NR⁶OH; (b) —CH₃, —CH₂F, or —CHF₂, which isunsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I,—NO₂, —CH═NR⁶, or —NR⁶OH; or (c) —H, -halo, —NO₂, —CN, or —NH₂; R³ is:(a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl, which issubstituted with one or more of —CH═NR⁶ or —NR⁶OH; or (b) —(CH₂)_(m)OR⁶,which is unsubstituted or substituted with one or more of —CN, —OH,-halo, —NO₂, —CH═NR⁶, or —NR OH; R⁴ is —H; R⁵ is: (a) —(C₂-C₆)alkenyl,or —(C₂-C₆)alkynyl; or (b) —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₆)aryl, —(C₁₀)aryl, —(C₁₄)aryl, —(C₃-C₇)heterocycle,—(C₁-C₆)alkyl(C₆)aryl, —(C₁-C₆)alkyl(C₁₀)aryl, —(C₁-C₆)alkyl(C₁₄)aryl,—(C₁-C₆)alkyl(C₃-C₇)heterocycle, —(C₂-C₆)alkenyl(C₆)aryl,—(C₂-C₆)alkenyl(C₁₀)aryl, —(C₂-C₆)alkenyl(C₁₄)aryl,—(C₂-C₆)alkenyl(C₃-C₇)heterocycle, —(C₂-C₆)alkynyl(C₃-C₈)cycloalkyl,—(C₂-C₆)alkynyl(C₅-C₈)cycloalkenyl, —(C₂-C₆)alkynyl(C₆)aryl,—(C₂-C₆)alkynyl(C₁₀)aryl, —(C₂-C₆)alkynyl(C₁₄)aryl, or—(C₂-C₆)alkynyl(C₃-C₇)heterocycle, which is unsubstituted or substitutedwith one or more R⁷ groups; each R⁶ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, —(C₆)aryl, —(C₃-C₅)heterocycle, —C(halo)₃, or—CH(halo)₂; each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(CH₂)_(n)(C₃-C₈)cycloalkyl,—(CH₂)_(n)(C₅-C₈)cycloalkenyl, —(CH₂)_(n)(C₆)aryl, —(CH₂)_(n)SR⁶,—(CH₂)_(n)CH(halo)₂, —(CH₂)_(n)C(halo)₃, -halo, or —(CH₂)_(n)OR⁶; m is 1or 2; and n is an integer ranging from 0 to
 2. 10. The method of claim9, further comprising administering an effective amount of an opioidanalgesic.
 11. The method of claim 9, further comprising administeringan effective amount of a non-opioid analgesic.
 12. The method of claim9, further comprising administering an effective amount of ananti-emetic agent.